Next Article in Journal
Estrogenic and Non-Estrogenic Disruptor Effect of Zearalenone on Male Reproduction: A Review
Next Article in Special Issue
Functional Characterization of Transgenic Mice Overexpressing Human 15-Lipoxygenase-1 (ALOX15) under the Control of the aP2 Promoter
Previous Article in Journal
Ginseng Sprouts Attenuate Mortality and Systemic Inflammation by Modulating TLR4/NF-κB Signaling in an LPS-Induced Mouse Model of Sepsis
Previous Article in Special Issue
Functional Characterization of Novel Bony Fish Lipoxygenase Isoforms and Their Possible Involvement in Inflammation
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 2
10.3390/ijms24021579
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Secretory Phospholipases A2, from Snakebite Envenoming to a Myriad of Inflammation Associated Human Diseases—What Is the Secret of Their Activity?

by
Fiorella Tonello
CNR of Italy, Neuroscience Institute, Viale G. Colombo 3, 35131 Padova, Italy
Int. J. Mol. Sci. 2023, 24(2), 1579; https://doi.org/10.3390/ijms24021579
Submission received: 14 December 2022 / Revised: 5 January 2023 / Accepted: 11 January 2023 / Published: 13 January 2023
(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)
Browse Figures
Review Reports Versions Notes

Abstract

:
Secreted phospholipases of type A2 (sPLA2s) are proteins of 14–16 kDa present in mammals in different forms and at different body sites. They are involved in lipid transformation processes, and consequently in various immune, inflammatory, and metabolic processes. sPLA2s are also major components of snake venoms, endowed with various toxic and pharmacological properties. The activity of sPLA2s is not limited to the enzymatic one but, through interaction with different types of molecules, they exert other activities that are still little known and explored, both outside and inside the cells, as they can be endocytosed. The aim of this review is to analyze three features of sPLA2s, yet under-explored, knowledge of which could be crucial to understanding the activity of these proteins. The first feature is their disulphide bridge pattern, which has always been considered immutable and necessary for their stability, but which might instead be modulable. The second characteristic is their ability to undergo various post-translational modifications that would control their interaction with other molecules. The third feature is their ability to participate in active molecular condensates both on the surface and within the cell. Finally, the implications of these features in the design of anti-inflammatory drugs are discussed.

1. Introduction

A phospholipase A2 (PLA2) is an enzyme that hydrolyzes the second ester bond of a phospholipid releasing a fatty acid and a lysophospholipid. Eucaryotic PLA2s are classified in intra- and extra-cellular or secreted. Secretory PLA2s (sPLA2s) are translated with a N-terminal signal peptide that is removed in the endoplasmic reticulum, and then they are translocated through the Golgi and secretory vesicle to the extracellular space. They are abundant in numerous human body fluids, in pancreatic juice, tears, seminal fluid, and some of them are detectable also in blood serum [1,2].
sPLA2s are also present in prokaryotes, and procaryotic and eukaryotic sPLA2s share the same mechanism of action, in which a water molecule, activated by the histidine residue (H48) of the active site, performs a nucleophilic attack on the sn2 carbonyl oxygen of the phospholipid [3]. The reaction intermediate is stabilized by a calcium ion coordinated by an aspartic acid residue (D49) and the calcium binding loop (GCxCGxG). According to the classification described by Schaloske and Dennis (2006) [4], sPLA2 of groups I, II, V and X, which share the 3D structure and disulphide bonding pattern, belong to a single structural class, later termed ‘conventional’, whereas group III sPLA2, which resemble the sPLA2 of bee venom, and group XII sPLA2, constitute a second and a third structural class and are considered atypical [5].
The best-known sPLA2 functions are the digestion of lipids, in the digestive system, and the antibacterial defense in various body sites, e.g., in the intestines, in tears. However, these proteins are involved in various inflammatory and lipid metabolism processes and consequently in numerous diseases, from metabolic and cardiovascular, to neurodegenerative and neuromuscular diseases. Table 1 shows the main tissues and diseases in which conventional sPLA2s are involved.
Important toxic components of the snake venoms are sPLA2s of group I and II. They are endowed with several toxic properties, among which the most widespread are hemotoxicity, myotoxicity, and neurotoxicity (Table 2). The homology between the phospholipases composing snake venoms and some human sPLA2s is very high, in some cases higher than the homology between human sPLA2s belonging to different subgroups [28]. Therefore, snake venom sPLA2s can be considered a reservoir of natural homologs, selected over millions of years for their toxic properties, which can help us understand the basic function and pathological features of human sPLA2s.
The biological activity of PLA2s, although they are involved in numerous pathologies, has not yet been fully understood. Firstly, because their enzymatic activity, well characterized in vitro, is more difficult to know in vivo because it is influenced by many local parameters, such as the type of lipids present, their accessibility, the micro-local calcium concentration, and interactions with other proteins and carbohydrates. Secondly, because sPLA2s perform other activities besides their enzymatic function. Natural sPLA2 homologs of snake venom lacking catalytic activity, as the aspartic acid residue (D49) in the active site is replaced by lysine (K49) or other amino acids, possess equal or even higher toxicity than their catalytically active counterparts. This non-catalytic activity of sPLA2s is even less known because it depends on a complex network of interactions with many other types of molecules. Finally, the activity of sPLA2s is not only expressed outside the cell because, following interaction with various surface receptors and co-receptors, sPLA2s are internalized [34].
In recent years, many reviews have been focused on these proteins, some addressing one group in particular, group IB [8], including IIA [13,14,16,35,36], II E, D, and F [18], as well as sPLA2s of group V [24] and group X [27], while others relate to the role of sPLA2s in macrophage modulation [37], in insulin resistance and metabolism [38], in acute lung injury [15], as targets of anti-inflammatory drugs [39], in viral diseases [40], and to their non-enzymatic activity [34]. Regarding the non-enzymatic activity of sPLA2s, Ivanušec et al. discussed the interaction of sPLA2s with soluble and membrane proteins, the signaling triggered by the interaction of sPLA2s with cell membrane receptors, and their internalization, intracellular transport, and localization [34]. This review examines three yet underexplored aspects of sPLA2s’ non-enzymatic activity: the role of the disulphide bridge pattern, which may not be as immutable, as has been assumed; the possibility that these proteins, when internalized in the cell, are targets of enzymes that introduce post-translational modifications that contribute to varying and controlling sPLA2 activity; and, third, the protein assemblies in which sPLA2s participate and their possible biological role. Finally, based on these three new features, the development of new drugs targeting sPLA2s in inflammation associated diseases will be discussed.

2. sPLA2s Possess a Specific Pattern of Disulphide Bonds That Could Be Modulable

Conventional sPLA2 share a pattern of disulphide, comprising five to eight bridges (Figure 1). The central part of this domain, consisting of four bridges, dates to the basal metazoan. The structural domain shared by these proteins is classified with the code cd00125 in the Conserved Domain Database (CDD, NCBI), and it comprises the functional sites for enzymatic activity: the active site and the calcium binding loop [3].
Most eukaryotic secreted proteins possess disulphide bridges [41], whose best-known function is to confer stability, but which are also often involved in modulating the activity of both secreted proteins and membrane receptors [42], such as in the process of virus internalization [43]. A mutagenesis study of each, one by one, of the seven disulphide bridges of bovine pancreatic sPLA2 (group IB), found that only one (the one that corresponds to number 8 in Figure 1) is crucial for the folding process, while the first bridge (n. 1 in Figure 1) is the most important for the protein stability upon denaturation with guanidinium chloride [44]. The stability of bridge n. 1 has also been confirmed by another group through studies of resistance to proteolysis with trypsin [42]. Only the deletion of bridge n. 3, the one that stabilizes the calcium binding loop, causes a sharp drop in enzyme activity, whereas bridge n. 2, the one in the most disordered part of the protein, is a highly strained chemical bond, and its deletion confers stability to the protein [44]. Intriguingly, bridge n. 2 has been identified as labile in two group IIA sPLAs, the human one and the PLA2 homologue of Bothrops pirajai, piratoxin-I, as it is present in some but not all structures of the proteins. This suggests that it can be an allosteric bridge, i.e., a bridge that confers different activities to the protein depending on its state, open or closed [45]. A labile bridge was also identified in a group I sPLA2 of Naja atra (Uniprot entry P00598), the one corresponding to number 8 in Figure 1 [45].
A labile disulphide bridge could be the object of attack by cysteines present in other proteins, which would thus form a permanent or temporary covalent bond with sPLA2s, capable of modulating their structure and activity, or involving them in protein complexes. Interestingly, a group II snake venom PLA2, ammodytoxin (Atx), has been reported to have a strong interaction with protein disulphide isomerase (PDI), a chaperone protein that catalyses the opening and closing of disulphide bridges. No covalent link has been found between the two, but it may be a short-lived link, or happen only under certain conditions [46]. Moreover, Atx interacts with cytochrome c oxidase in the mitochondria intermembrane space [47], whose import pathway recognizes proteins that are cysteine-rich, and it is based on a disulphide relay mechanism [48].
The enzymatic activity of human and mouse sPLA2 is inhibited by the presence of dithiothreitol, a reducing agent, but with different efficiency depending on the protein, probably due to a different resistance to the reduction of their disulphide bridges, or due to a persistence of enzymatic activity even after the opening of some bridges [49]. This implies that some of these proteins can also be active in a reducing environment, which is important considering that these proteins are internalized, and that the cytosolic environment is reducing [50]. In the case of Atx, it has been proven that it is also active under cytosolic conditions [51].
In summary, sPLA2s contain a highly conserved pattern of disulphide bridges, not all of which, however, are strictly necessary for the stability and catalytic activity of the protein. Some of these bridges, in particular the second bridge described in Figure 1, may be conserved because they are involved in as yet unknown modulations of the activity of the sPLA2 through interactions with reducing agents or with reduced cysteines of other proteins.

3. sPLA2 Activity Can Be Controlled by Post Translational Modifications

sPLA2s are expressed with a N-terminal signal peptide that causes them to be translocated during synthesis into the endoplasmic reticulum, where they acquire the correct three-dimensional structure, and then they are secreted in a conventional manner via secretion vesicles that fuse with the plasma membrane. sPLA2s are not known to undergo post-translational modifications in the ER and Golgi, apart from disulphide bridge closure and signal peptide removal, and in the extra-cellular environment, apart from the removal of a pro-peptide in the case of group I and X PLA2s [1,27]. However, when they are internalized and translocated into the cytosol, they enter in an environment rich in enzymes that can modify them and thus change their activities and molecular interactions.
There are no studies dedicated to the PTMs of sPLA2s, but some have been identified in studies detecting PTMs present in all cellular proteins (Figure 2). Several phosphorylation sites have been identified in group IIE and IID human sPLA2s [52,53]. Group IIA PLA2 was found to be phosphorylated at tyrosine 86 [54], ubiquitinated at lysine 82 [55], and sumoylated at lysine 128 [56]. Sumoylation is a modification that is more frequent in proteins that are transported to the nucleus, and PLA2-IIA can have a nuclear localization.
The possibility that sPLA2s undergo PTM should be considered when studying the molecular effects caused by pathological genetic variants of these proteins [57]. The R143H mutation of PLA2-IIA (R123H considers the numbering without the signal peptide), found in two infants affected by acute respiratory distress syndrome (ARDS) [12], modifies a possible phosphorylation site recognized by cyclin-dependent protein kinase (CDK) ([ST])P[RK]), where a serine or a threonine is followed by a proline at position +1 and a basic residue at position +2 [58]. CDKs are involved in other processes besides cell division, e.g., in the regulation of the immune system [59], so it would be worth investigating whether the pathogenicity of the R143H mutation is due to the alteration of a CDK phosphorylation site. The S80G mutation of PLA2-IID (S80G considers the numbering without the signal peptide), associated with weight loss in subjects with chronic obstructive pulmonary disease (COPD) [19], could alter a phosphorylation site by glycogen synthase kinase-3 (GSK3), a kinase involved in numerous biological processes and diseases [59], which is also a regulator of metabolic pathways [60] involved in muscle atrophy in COPD [61].
A wealth of pathological variants of these proteins are present in animal venoms. By comparing the sequence of sPLA2s from snake venom with the corresponding human homologues, differences emerged in the short linear motifs (SLiMs) conserved in the two protein categories. This comparison showed that human proteins differ from animal venom in the presence of SLiMs susceptible to undergoing PTMs by the S/T kinases CDK, GSK3, PKA, MAPK, by tyrosine kinases, and by Pin1, a [ST] phosphorylation-regulated prolyl isomerase [62]. These differences in the sites subjected to PTMs may give the toxins the possibility of establishing different molecular interactions than mammalian sPLA2s and/or confer different resistance to degradative processes via the ubiquitin-proteasome pathway or micro autophagy.
In conclusion, to investigate the biological action of sPLA2s, it is important to consider that, when they are imported into the cytosol, they may undergo PTMs that affect their molecular interactions and biological activity. The pathological action of human variants of sPLA2s, and of toxic sPLA2s present in animal venoms, could also be due to mutations of their PTM sites.

4. sPLA2s Are Globular Proteins, but They Can Form Active Condensates

The sPLA2s interact with different types of proteins, both extra- and intracellular [34]. Basic phospholipases also interact with heparan sulphate proteoglycans (HSPGs) on the cell surface [21,63,64,65,66]. Some sPLA2s can also form catalytically active oligomers when they come into contact with lipid membranes [67], or amyloid-like assemblies on the cell surface, implicated in their internalization [68]. These multiple interactions suggest that sPLA2s are not proteins that establish 1:1 interaction, but rather participate in molecular complexes. Molecular complexes formed by liquid–liquid phase separation (LLPS) are considered membraneless organelles (MLOs) or biomolecular condensates. Several intracellular MLOs are known to perform a variety of functions, from chromatin organization to ribosome assembly, to mRNA transport and metabolism [69].
Two-dimensional condensates can also be formed on the membrane of the cell or internal organelles [70]. Recently, the formation of an extracellular condensate between fibroblast growth factor and HSPG has also been observed, which serves to enrich the growth factor around its receptor and trigger signaling transduction [70]. The same phenomenon can happen with the sPLA2s that interact with HSPGs on the cell surface, and activate an intracellular signal by yet unknown mechanisms, which also triggers their internalization. For example, group II human sPLA2 interacts with glypican-1 (GPC-1), a transmembrane protein modified with heparan sulphates, and thanks to this interaction, is internalised and localised in the paranuclear zone [66]. In addition to HSPGs, two group II sPLA2s, the human one and a PLA2-like myotoxin, interact with two proteins, nucleolin (NCL) and vimentin (VIM), known for their ability to establish multiple molecular interactions both inside the cell, where they are normally found, and on the cell surface, where they are secreted by unconventional mechanisms [36,68]. On the cell surface, NCL and VIM interact with different membrane receptors, forming complexes that mediate the internalization of different types of viruses or other pathogens and proteins [71,72]. Membrane proteins with which NCL and VIM interact include integrins alpha 3, alpha 4, beta 1, and beta 3 (ITGA4, ITGA6, ITGB1, and ITGB3), the epidermal growth factor receptor (EGFR), and glypican-1 (GPC-1), all identified as group II sPLA2 receptors [34] (Figure 3). Group II sPLA2s can be assumed to participate in cell surface molecular complexes involving various membrane proteins, proteoglycans, and secreted factors. Other sPLAs can be involved in these kind of complexes in the cell surface, i.e., Group V human PLA2 was suggested to induce the release of proangiogenic and antiangiogenic factors by interacting with PLA2R1 and heparan sulfate proteoglycans, or with αVβ3 and α4β1 integrins [64].
Because of interaction with the surface receptors described above, sPLA2s are internalized and transported to the paranuclear, or in some cases, even nuclear zones [24,66,74]. The intracellular function of sPLA2s is still poorly understood, but based on the intracellular interactions they establish, it can be assumed that they participate in protein complexes that are formed to produce lipid derivatives, such as prostaglandins and leukotrienes. Many lipid intermediates are highly reactive and have a very short half-life, which is why the enzymes that transform them are assembled into complexes that allow lipid transformation to be completed rapidly and in the same cellular micro zone [75]. Within the cell, sPLA2s colocalise with cytosolic phospholipase, cyclooxygenase 2, and lipoxygenase 12 [66,76,77,78,79]. In addition, several sPLA2 receptors or coreceptors interact with and regulate the assembly of lipid metabolism enzymes: proteoglycans, integrins, and vimentin [76,79,80]. NCL and EFGR, on the other hand, interact with mRNAs of lipid metabolism enzymes and presumably regulate their translation [81,82].
The toxic action of snake sPLA2s is not yet fully understood. At the level of the plasma membrane, in the case of catalytically active phospholipases, one hypothesis is that the enzyme action may destabilize membranes, in the case of myotoxins, or induce the fusion of neurotransmitter vesicles with the synaptic terminal, in the case of neurotoxins [28,83]. In the case of phospholipase-like proteins, one hypothesis is that they can destabilize membranes through interaction with negatively charged lipids, causing an ionic imbalance in the cell. A mechanism analogous to this has also been hypothesized for proteins that form amyloid oligomers, but, in recent years, an alternative hypothesis has emerged: that condensates of these proteins on the plasma membrane may activate harmful intracellular signaling. This alternative hypothesis could also explain the action of snake sPLAs, which activate various signal cascades, thus triggering inflammatory responses and, at high concentrations, even cell death [84,85]. Several venom sPLA2s are internalized and, similar to human sPLA2s, localized in the nuclear or paranuclear zone [68,86,87], where they can alter molecular complexes involved in lipid metabolism and, for instance, cause excess production of reactive oxygen species or toxic lipid derivatives. At the mitochondrial level, Šribar et al. demonstrated that Atx interacts with and inhibits cytochrome c oxidase, a large transmembrane protein complex [47]. Another aspect to consider is the interaction of catalytically inactive sPLA2s with specific lipids. Bothrops asper myotoxin-II has a high affinity for phosphatidic acid [83], a lipid that regulates the activity of several integral and peripheral membrane proteins [88] and is also involved in LLPS processes [89].
To summarize, the multiple interactions established by sPLA2s with different types of molecules, lipids, carbohydrates, membrane receptors, co-receptors, and intracellular enzymes mean that they can participate in the formation of molecular condensates both on the cell surface and intracellularly. Understanding how these complexes are formed and broken down, as well as their function, will be crucial to understanding the activity of sPLA2s.

5. How to Target sPLA2s in Inflammation-Associated Human Diseases

Most, if not all, diseases in which sPLA2s are involved have an inflammatory component, and A2-type phospholipases, mainly sPLA2s, are considered an important target in the development of anti-inflammatory drugs, as they arbitrate the release of fatty acids that are then converted into inflammatory mediators. Today, inflammation is mainly treated with cyclooxygenase 1 and 2 inhibitors that act downstream of the action of sPLA2s, or with cortisone drugs that act instead upstream of sPLA2s production, as they regulate the expression of different inflammatory agents. Both types of treatments have important side effects, ranging from gastrointestinal and cardiovascular disorders in the case of cyclooxygenase inhibitors, to disorders of various kinds in the case of cortisone drugs, as this class of proteins regulates various physiological processes that are consequently altered [39].
Inhibitors of sPLA2 enzymatic activity have not yielded the desired results in clinical trials [90]. One possible reason is that they are not sufficient to block the enzymatic activity of these proteins. Moreover, their activity is extremely specific, depending on the micro-zone of action, and on the complex of molecular interactions they establish. Knowing the interactions and any molecular condensates in which sPLA2 is involved is of paramount importance. Molecular condensates regulate a variety of cellular activities and are involved in numerous pathological processes [69,91], therefore, they are being studied for the development of molecules that can induce their formation, alter, or even dissolve them [92].
Examples of molecules that interfere with molecular interactions of sPLA2s already exist: an aptamer that binds to NCL, a disordered co-receptor protein of a snake venom sPLA2, preventing its internalization into the cell and protecting it from its toxic effects [68]; and pentapeptides, which mimic a central stretch (63–67 in Figure 2) of Group II sPLA2s, one of which, cyclic, is in clinical trial as a drug against prostate cancer [36,93]. Interestingly, tract 63–67 includes a tyrosine, conserved in groups IIA, IID, and IIE sPLA2s, which has been identified as phosphorylated in sPLA2s IIA and IIE by high throughput investigations (see Section 3 and Figure 2), suggesting that this peptide may act by interfering with this PTM.
In the future, we will see an increase in the development and creation of molecules acting on molecular condensates [94], and we will need a system for screening these molecules also on models of action of sPLA2s. Such a system can be realized by treating cellular cultures with recombinant sPLA2s conjugated to fluorophores [68,86]. In this way, the molecular condensates in which the sPLA2s participate can be visualized, and the effects of the condensate modifiers can be monitored via live imaging.
To sum up, the development of new anti-inflammatory drugs targeting sPLA2s will have to consider the complexity of their action and regulation, as well as the multiple molecular interactions they can establish. To this end, new experimental models will be required to test the action of compounds that affect the formation and stability of the molecular complexes of which they take part.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Lambeau, G.; Gelb, M.H. Biochemistry and Physiology of Mammalian Secreted Phospholipases A2. Annu. Rev. Biochem. 2008, 77, 495–520. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Murakami, M.; Taketomi, Y.; Miki, Y.; Sato, H.; Yamamoto, K.; Lambeau, G. Emerging Roles of Secreted Phospholipase A2 Enzymes: The 3rd Edition. Biochimie 2014, 107 Pt A, 105–113. [Google Scholar] [CrossRef] [PubMed]
  3. Nevalainen, T.J.; Cardoso, J.C.; Riikonen, P.T. Conserved Domains and Evolution of Secreted Phospholipases A(2). FEBS J. 2012, 279, 636–649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Schaloske, R.H.; Dennis, E.A. The Phospholipase A2 Superfamily and Its Group Numbering System. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2006, 1761, 1246–1259. [Google Scholar] [CrossRef] [PubMed]
  5. Murakami, M.; Taketomi, Y.; Sato, H.; Yamamoto, K. Secreted Phospholipase A2 Revisited. J. Biochem. 2011, 150, 233–255. [Google Scholar] [CrossRef] [Green Version]
  6. Suzuki, N.; Ishizaki, J.; Yokota, Y.; Higashino, K.I.; Ono, T.; Ikeda, M.; Fujii, N.; Kawamoto, K.; Hanasaki, K. Structures, Enzymatic Properties, and Expression of Novel Human and Mouse Secretory Phospholipase A(2)S. J. Biol. Chem. 2000, 275, 5785–5793. [Google Scholar] [CrossRef] [Green Version]
  7. Yagami, T.; Yamamoto, Y.; Koma, H. The Role of Secretory Phospholipase A2; in the Central Nervous System and Neurological Diseases. Mol. Neurobiol. 2014, 49, 863–876. [Google Scholar] [CrossRef]
  8. Hui, D.Y. Group 1B Phospholipase A 2 in Metabolic and Inflammatory Disease Modulation. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2019, 1864, 784–788. [Google Scholar] [CrossRef]
  9. Karlsson Linnér, R.; Mallard, T.T.; Barr, P.B.; Sanchez-Roige, S.; Madole, J.W.; Driver, M.N.; Poore, H.E.; de Vlaming, R.; Grotzinger, A.D.; Tielbeek, J.J.; et al. Multivariate Analysis of 1.5 Million People Identifies Genetic Associations with Traits Related to Self-Regulation and Addiction. Nat. Neurosci. 2021, 24, 1367–1376. [Google Scholar] [CrossRef]
  10. Moses, G.S.D.; Jensen, M.D.; Lue, L.F.; Walker, D.G.; Sun, A.Y.; Simonyi, A.; Sun, G.Y. Secretory PLA2-IIA: A New Inflammatory Factor for Alzheimer’s Disease. J. Neuroinflamm. 2006, 3, 28. [Google Scholar] [CrossRef]
  11. Hathout, Y.; Brody, E.; Clemens, P.R.; Cripe, L.; DeLisle, R.K.; Furlong, P.; Gordish-Dressman, H.; Hache, L.; Henricson, E.; Hoffman, E.P.; et al. Large-Scale Serum Protein Biomarker Discovery in Duchenne Muscular Dystrophy. Proc. Natl. Acad. Sci. USA 2015, 112, 7153–7158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Righino, B.; Minucci, A.; Pirolli, D.; Capoluongo, E.; Conti, G.; De Luca, D.; Rosa, M.C. De In Silico Investigation of the Molecular Effects Caused by R123H Variant in Secretory Phospholipase A2-IIA Associated with ARDS. J. Mol. Graph. Model. 2018, 81, 68–76. [Google Scholar] [CrossRef] [PubMed]
  13. Dore, E.; Boilard, E. Roles of Secreted Phospholipase A. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2019, 1864, 789–802. [Google Scholar] [CrossRef] [PubMed]
  14. Scott, K.F.; Mann, T.J.; Fatima, S.; Sajinovic, M.; Razdan, A.; Kim, R.R.; Cooper, A.; Roohullah, A.; Bryant, K.J.; Gamage, K.K.; et al. Human Group Iia Phospholipase A2—Three Decades on from Its Discovery. Molecules 2021, 26, 7267. [Google Scholar] [CrossRef]
  15. Letsiou, E.; Htwe, Y.M.; Dudek, S.M. Secretory Phospholipase A2 Enzymes in Acute Lung Injury. Cell Biochem. Biophys. 2021, 79, 609–617. [Google Scholar] [CrossRef]
  16. Taketomi, Y.; Miki, Y.; Murakami, M. Old but New: Group IIA Phospholipase A2 as a Modulator of Gut Microbiota. Metabolites 2022, 12, 352. [Google Scholar] [CrossRef]
  17. Ishizaki, J.; Suzuki, N.; Higashino, K.I.; Yokota, Y.; Ono, T.; Kawamoto, K.; Fujii, N.; Arita, H.; Hanasaki, K. Cloning and Characterization of Novel Mouse and Human Secretory Phospholipase A(2)S. J. Biol. Chem. 1999, 274, 24973–24979. [Google Scholar] [CrossRef] [Green Version]
  18. Murakami, M.; Miki, Y.; Sato, H.; Murase, R.; Taketomi, Y.; Yamamoto, K. Group IID, IIE, IIF and III Secreted Phospholipase A 2 S. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2019, 1864, 803–818. [Google Scholar] [CrossRef]
  19. Khan, M.I.; Gupta, A.K.; Kumar, D.R.; Kumar, M.; Ethayathulla, A.S.; Hariprasad, G. Molecular Modeling of Gly80 and Ser80 Variants of Human Group IID Phospholipase A2 and Their Receptor Complexes: Potential Basis for Weight Loss in Chronic Obstructive Pulmonary Disease. J. Mol. Model. 2016, 22, 232. [Google Scholar] [CrossRef]
  20. Valentin, E.; Singer, A.G.; Ghomashchi, F.; Lazdunski, M.; Gelb, M.H.; Lambeau, G. Cloning and Recombinant Expression of Human Group IIF-Secreted Phospholipase A(2). Biochem. Biophys. Res. Commun. 2000, 279, 223–228. [Google Scholar] [CrossRef]
  21. Murakami, M.; Yoshihara, K.; Shimbara, S.; Lambeau, G.; Singer, A.; Gelb, M.H.; Sawada, M.; Inagaki, N.; Nagai, H.; Kudo, I. Arachidonate Release and Eicosanoid Generation by Group IIE Phospholipase A2. Biochem. Biophys. Res. Commun. 2002, 292, 689–696. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Sergouniotis, P.I.; Davidson, A.E.; MacKay, D.S.; Lenassi, E.; Li, Z.; Robson, A.G.; Yang, X.; Kam, J.H.; Isaacs, T.W.; Holder, G.E.; et al. Biallelic Mutations in PLA2G5, Encoding Group v Phospholipase A 2, Cause Benign Fleck Retina. Am. J. Hum. Genet. 2011, 89, 782–791. [Google Scholar] [CrossRef] [Green Version]
  23. Rubio, J.M.; Rodríguez, J.P.; Gil-de-Gómez, L.; Guijas, C.; Balboa, M.A.; Balsinde, J. Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids. J. Immunol. 2015, 194, 3327–3339. [Google Scholar] [CrossRef] [Green Version]
  24. Samuchiwal, S.K.; Balestrieri, B. Harmful and Protective Roles of Group V Phospholipase A2: Current Perspectives and Future Directions. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2019, 1864, 819–826. [Google Scholar] [CrossRef] [PubMed]
  25. Cupillard, L.; Koumanov, K.; Mattéi, M.G.; Lazdunski, M.; Lambeau, G. Cloning, Chromosomal Mapping, and Expression of a Novel Human Secretory Phospholipase A2. J. Biol. Chem. 1997, 272, 15745–15752. [Google Scholar] [CrossRef] [Green Version]
  26. Sato, H.; Isogai, Y.; Masuda, S.; Taketomi, Y.; Miki, Y.; Kamei, D.; Hara, S.; Kobayashi, T.; Ishikawa, Y.; Ishii, T.; et al. Physiological Roles of Group X-Secreted Phospholipase A2 in Reproduction, Gastrointestinal Phospholipid Digestion, and Neuronal Function. J. Biol. Chem. 2011, 286, 11632–11648. [Google Scholar] [CrossRef] [Green Version]
  27. Nolin, J.D.; Murphy, R.C.; Gelb, M.H.; Altemeier, W.A.; Henderson, W.R.; Hallstrand, T.S. Function of Secreted Phospholipase A2 Group-X in Asthma and Allergic Disease. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2019, 1864, 827–837. [Google Scholar] [CrossRef] [PubMed]
  28. Tonello, F.; Rigoni, M. Cellular Mechanisms of Action of Snake Phospholipase A2 Toxins; Inagaki, H., Vogel, C.W., Mukherjee, A., Rahmy, T., Eds.; Snake Venoms; Part of the Toxinology; Springer: Dordrecht, The Netherlands, 2017; pp. 49–65. [Google Scholar] [CrossRef]
  29. Mamede, C.C.N.; de Sousa Simamoto, B.B.; da Cunha Pereira, D.F.; de Oliveira Costa, J.; Ribeiro, M.S.M.; de Oliveira, F. Edema, Hyperalgesia and Myonecrosis Induced by Brazilian Bothropic Venoms: Overview of the Last Decade. Toxicon 2020, 187, 10–18. [Google Scholar] [CrossRef]
  30. Kini, R.M. Structure-Function Relationships and Mechanism of Anticoagulant Phospholipase A2 Enzymes from Snake Venoms. Toxicon 2005, 45, 1147–1161. [Google Scholar] [CrossRef]
  31. Larréché, S.; Chippaux, J.P.; Chevillard, L.; Mathé, S.; Résière, D.; Siguret, V.; Mégarbane, B. Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders. Int. J. Mol. Sci. 2021, 22, 9643. [Google Scholar] [CrossRef] [PubMed]
  32. Lomonte, B.; Gutiérrez, J.M. Phospholipases A2 from Viperidae Snake Venoms: How Do They Induce Skeletal Muscle Damage? Acta Chim. Slov. 2011, 58, 647–659. [Google Scholar] [PubMed]
  33. Šribar, J.; Oberčkal, J.; Križaj, I. Understanding the Molecular Mechanism Underlying the Presynaptic Toxicity of Secreted Phospholipases A(2): An Update. Toxicon 2014, 89, 9–16. [Google Scholar] [CrossRef]
  34. Ivanušec, A.; Šribar, J.; Križaj, I. Secreted Phospholipases A2–Not Just Enzymes: Revisited. Int. J. Biol. Sci. 2022, 18, 873–888. [Google Scholar] [CrossRef]
  35. van Hensbergen, V.P.; Wu, Y.; van Sorge, N.M.; Touqui, L. Type IIA Secreted Phospholipase A2 in Host Defense against Bacterial Infections. Trends Immunol. 2020, 41, 313–326. [Google Scholar] [CrossRef]
  36. Kim, R.R.; Chen, Z.; Mann, T.J.; Bastard, K.; Scott, K.F.; Church, W.B. Structural and Functional Aspects of Targeting the Secreted Human Group IIA Phospholipase A2. Molecules 2020, 25, 4459. [Google Scholar] [CrossRef]
  37. Galdiero, M.R.; Mormile, I.; Granata, F.; Loffredo, S.; Detoraki, A.; Della Casa, F.; Trocchia, M.L.; Ventrici, A.; de Paulis, A.; Rossi, F.W. Functional Modulation of Human Macrophages by Secreted Phospholipases A2: Implications in Cancer. Biomedicines 2022, 10, 2763. [Google Scholar] [CrossRef] [PubMed]
  38. Kuefner, M.S. Secretory Phospholipase A2s in Insulin Resistance and Metabolism. Front. Endocrinol. 2021, 12, 732726. [Google Scholar] [CrossRef]
  39. Sales, T.A.; Marcussi, S.; Ramalho, T.C. Current Anti-Inflammatory Therapies and the Potential of Secretory Phospholipase A2 Inhibitors in the Design of New Anti-Inflammatory Drugs: A Review of 2012–2018. Curr. Med. Chem. 2020, 27, 477–497. [Google Scholar] [CrossRef]
  40. Pungerčar, J.; Bihl, F.; Lambeau, G.; Križaj, I. What Do Secreted Phospholipases A2 Have to Offer in Combat against Different Viruses up to SARS-CoV-2? Biochimie 2021, 189, 40–50. [Google Scholar] [CrossRef]
  41. Bošnjak, I.; Bojović, V.; Šegvić-Bubić, T.S.; Bielen, A. Occurrence of Protein Disulfide Bonds in Different Domains of Life: A Comparison of Proteins from the Protein Data Bank. Protein Eng. Des. Sel. 2014, 27, 65–72. [Google Scholar] [CrossRef] [PubMed]
  42. Janssen, M.J.W.; Verheij, H.M.; Slotboom, A.J.; Egmond, M.R. Engineering the Disulphide Bond Patterns of Secretory Phospholipases A2 into Porcine Pancreatic Isozyme. The Effects on Folding, Stability and Enzymatic Properties. Eur. J. Biochem. 1999, 261, 197–207. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Mathys, L.; Balzarini, J. The Role of Cellular Oxidoreductases in Viral Entry and Virus Infection-Associated Oxidative Stress: Potential Therapeutic Applications. Expert Opin. Ther. Targets 2016, 20, 123–143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Zhu, H.; Dupureur, C.M.; Zhang, X.; Tsai, M.D. Phospholipase A2 Engineering. The Roles of Disulfide Bonds in Structure, Conformational Stability, and Catalytic Function. Biochemistry 1995, 34, 15307–15314. [Google Scholar] [CrossRef]
  45. Pijning, A.E.; Chiu, J.; Yeo, R.X.; Wong, J.W.H.; Hogg, P.J. Identification of Allosteric Disulfides from Labile Bonds in X-ray Structures. R. Soc. Open Sci. 2018, 5, 171058. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Šribar, J.; Anderluh, G.; Fox, J.W.; Križaj, I. Protein Disulphide Isomerase Binds Ammodytoxin Strongly: Possible Implications for Toxin Trafficking. Biochem. Biophys. Res. Commun. 2005, 329, 733–737. [Google Scholar] [CrossRef]
  47. Šribar, J.; Kovačič, L.; Oberčkal, J.; Ivanušec, A.; Petan, T.; Fox, J.W.; Križaj, I. The Neurotoxic Secreted Phospholipase A2 from the Vipera a. Ammodytes Venom Targets Cytochrome c Oxidase in Neuronal Mitochondria. Sci. Rep. 2019, 9, 283. [Google Scholar] [CrossRef] [Green Version]
  48. Dickson-Murray, E.; Nedara, K.; Modjtahedi, N.; Tokatlidis, K. The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space. Antioxidants 2021, 10, 592. [Google Scholar] [CrossRef]
  49. Singer, A.G.; Ghomashchi, F.; Le Calvez, C.; Bollinger, J.; Bezzine, S.; Rouault, M.; Sadilek, M.; Nguyen, E.; Lazdunski, M.; Lambeau, G.; et al. Interfacial Kinetic and Binding Properties of the Complete Set of Human and Mouse Groups I, II, V, X, and XII Secreted Phospholipases A2. J. Biol. Chem. 2002, 277, 48535–48549. [Google Scholar] [CrossRef] [Green Version]
  50. López-Mirabal, H.R.; Winther, J.R. Redox Characteristics of the Eukaryotic Cytosol. Biochim. Biophys. Acta 2008, 1783, 629–640. [Google Scholar] [CrossRef]
  51. Petrovič, U.; Šribar, J.; Pariš, A.; Rupnik, M.; Kržan, M.; Vardjan, N.; Gubenšek, F.; Zorec, R.; Križaj, I. Ammodytoxin, a Neurotoxic Secreted Phospholipase A(2), Can Act in the Cytosol of the Nerve Cell. Biochem. Biophys. Res. Commun. 2004, 324, 981–985. [Google Scholar] [CrossRef]
  52. Li, J.; Rix, U.; Fang, B.; Bai, Y.; Edwards, A.; Colinge, J.; Bennett, K.L.; Gao, J.; Song, L.; Eschrich, S.; et al. A Chemical and Phosphoproteomic Characterization of Dasatinib Action in Lung Cancer. Nat. Chem. Biol. 2010, 6, 291–299. [Google Scholar] [CrossRef] [Green Version]
  53. Hornbeck, P.V.; Zhang, B.; Murray, B.; Kornhauser, J.M.; Latham, V.; Skrzypek, E. PhosphoSitePlus, 2014: Mutations, PTMs and Recalibrations. Nucleic Acids Res. 2015, 43, D512–D520. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Artemenko, K.A.; Lind, S.B.; Elfineh, L.; Mayrhofer, C.; Zubarev, R.A.; Bergquist, J.; Pettersson, U. Optimization of Immunoaffinity Enrichment and Detection: Toward a Comprehensive Characterization of the Phosphotyrosine Proteome of K562 Cells by Liquid Chromatography-Mass Spectrometry. Analyst 2011, 136, 1971–1978. [Google Scholar] [CrossRef] [PubMed]
  55. Udeshi, N.D.; Svinkina, T.; Mertins, P.; Kuhn, E.; Mani, D.R.; Qiao, J.W.; Carr, S.A. Refined Preparation and Use of Anti-Diglycine Remnant (K-ε-GG) Antibody Enables Routine Quantification of 10,000s of Ubiquitination Sites in Single Proteomics Experiments. Mol. Cell. Proteom. 2013, 12, 825–831. [Google Scholar] [CrossRef] [Green Version]
  56. Hendriks, I.A.; D’Souza, R.C.J.; Yang, B.; Verlaan-De Vries, M.; Mann, M.; Vertegaal, A.C.O. Uncovering Global SUMOylation Signaling Networks in a Site-Specific Manner. Nat. Struct. Mol. Biol. 2014, 21, 927–936. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Khan, M.I.; Hariprasad, G. Human Secretary Phospholipase A2 Mutations and Their Clinical Implications. J. Inflamm. Res. 2020, 13, 551–561. [Google Scholar] [CrossRef] [PubMed]
  58. Brown, N.R.; Noble, M.E.M.; Endicott, J.A.; Johnson, L.N. The Structural Basis for Specificity of Substrate and Recruitment Peptides for Cyclin-Dependent Kinases. Nat. Cell Biol. 1999, 1, 438–443. [Google Scholar] [CrossRef]
  59. Beurel, E.; Grieco, S.F.; Jope, R.S. Glycogen Synthase Kinase-3 (GSK3): Regulation, Actions, and Diseases. Pharmacol. Ther. 2015, 148, 114–131. [Google Scholar] [CrossRef] [Green Version]
  60. Wang, L.; Li, J.; Di, L.J. Glycogen Synthesis and beyond, a Comprehensive Review of GSK3 as a Key Regulator of Metabolic Pathways and a Therapeutic Target for Treating Metabolic Diseases. Med. Res. Rev. 2022, 42, 946–982. [Google Scholar] [CrossRef]
  61. Verhees, K.J.P.; Pansters, N.A.M.; Baarsma, H.A.; Remels, A.H.V.; Haegens, A.; de Theije, C.C.; Schols, A.M.W.J.; Gosens, R.; Langen, R.C.J. Pharmacological Inhibition of GSK-3 in a Guinea Pig Model of LPS-Induced Pulmonary Inflammation: II. Effects on Skeletal Muscle Atrophy. Respir. Res. 2013, 14, 117. [Google Scholar] [CrossRef] [Green Version]
  62. Peggion, C.; Tonello, F. Short Linear Motifs Characterizing Snake Venom and Mammalian Phospholipases A2. Toxins 2021, 13, 290. [Google Scholar] [CrossRef]
  63. Murakami, M.; Yoshihara, K.; Shimbara, S.; Gelb, G.L.M.H.; Singer, A.G.; Sawada, M.; Inagaki, N.; Nagai, H.; Ishihara, M.; Ishikawa, Y.; et al. Cellular Arachidonate-Releasing Function and Inflammation-Associated Expression of Group IIF Secretory Phospholipase A2. J. Biol. Chem. 2002, 277, 19145–19155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Loffredo, S.; Borriello, F.; Iannone, R.; Ferrara, A.L.; Galdiero, M.R.; Gigantino, V.; Esposito, P.; Varricchi, G.; Lambeau, G.; Cassatella, M.A.; et al. Group V Secreted Phospholipase A2 Induces the Release of Proangiogenic and Antiangiogenic Factors by Human Neutrophils. Front. Immunol. 2017, 8, 443. [Google Scholar] [CrossRef] [Green Version]
  65. Gambero, A.; Landucci, E.C.T.; Toyama, M.H.; Marangoni, S.; Giglio, J.R.; Nader, H.B.; Dietrich, C.P.; De Nucci, G.; Antunes, E. Human Neutrophil Migration in Vitro Induced by Secretory Phospholipases A2: A Role for Cell Surface Glycosaminoglycans. Biochem. Pharmacol. 2002, 63, 65–72. [Google Scholar] [CrossRef] [PubMed]
  66. Murakami, M.; Kambe, T.; Shimbara, S.; Yamamoto, S.; Kuwata, H.; Kudo, I. Functional Association of Type IIA Secretory Phospholipase A(2) with the Glycosylphosphatidylinositol-Anchored Heparan Sulfate Proteoglycan in the Cyclooxygenase-2-Mediated Delayed Prostanoid-Biosynthetic Pathway. J. Biol. Chem. 1999, 274, 29927–29936. [Google Scholar] [CrossRef] [Green Version]
  67. Code, C.; Domanov, Y.; Jutila, A.; Kinnunen, P.K.J. Amyloid-Type Fiber Formation in Control of Enzyme Action: Interfacial Activation of Phospholipase A2. Biophys. J. 2008, 95, 215–224. [Google Scholar] [CrossRef] [Green Version]
  68. Massimino, M.L.; Simonato, M.; Spolaore, B.; Franchin, C.; Arrigoni, G.; Marin, O.; Monturiol-Gross, L.; Fernández, J.; Lomonte, B.; Tonello, F. Cell Surface Nucleolin Interacts with and Internalizes Bothrops Asper Lys49 Phospholipase A. Sci. Rep. 2018, 8, 10619. [Google Scholar] [CrossRef] [Green Version]
  69. Nesterov, S.V.; Ilyinsky, N.S.; Uversky, V.N. Liquid-Liquid Phase Separation as a Common Organizing Principle of Intracellular Space and Biomembranes Providing Dynamic Adaptive Responses. Biochim. Biophys. Acta Mol. Cell Res. 2021, 1868, 119102. [Google Scholar] [CrossRef] [PubMed]
  70. Xue, S.; Zhou, F.; Zhao, T.; Zhao, H.; Wang, X.; Chen, L.; Li, J.P.; Luo, S.Z. Phase Separation on Cell Surface Facilitates BFGF Signal Transduction with Heparan Sulphate. Nat. Commun. 2022, 13, 1112. [Google Scholar] [CrossRef]
  71. Tonello, F.; Massimino, M.L.; Peggion, C. Nucleolin: A Cell Portal for Viruses, Bacteria, and Toxins. Cell. Mol. Life Sci. 2022, 79, 271. [Google Scholar] [CrossRef]
  72. Paulin, D.; Lilienbaum, A.; Kardjian, S.; Agbulut, O.; Li, Z. Vimentin: Regulation and Pathogenesis. Biochimie 2022, 197, 96–112. [Google Scholar] [CrossRef] [PubMed]
  73. Bean, D.M.; Heimbach, J.; Ficorella, L.; Micklem, G.; Oliver, S.G.; Favrin, G. EsyN: Network Building, Sharing and Publishing. PLoS ONE 2014, 9, e106035. [Google Scholar] [CrossRef] [PubMed]
  74. Birts, C.N.; Barton, C.H.; Wilton, D.C. A Catalytically Independent Physiological Function for Human Acute Phase Protein Group IIA Phospholipase A2: Cellular Uptake Facilitates Cell Debris Removal. J. Biol. Chem. 2008, 283, 5034–5045. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Dennis, E.A.; Norris, P.C. Eicosanoid Storm in Infection and Inflammation. Nat. Rev. Immunol. 2015, 15, 511–523. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Kumar Dilly, A.; Tang, K.; Guo, Y.; Joshi, S.; Ekambaram, P.; Maddipati, K.R.; Cai, Y.; Tucker, S.C.; Honn, K.V. Convergence of Eicosanoid and Integrin Biology: Role of Src in 12-LOX Activation. Exp. Cell Res. 2017, 351, 1–10. [Google Scholar] [CrossRef] [Green Version]
  77. Martin, R.; Gutierrez, B.; Cordova, C.; Roman, A.S.; Alvarez, Y.; Hernandez, M.; Cachofeiro, V.; Nieto, M.L. Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation-Fibrosis Link. Cells 2020, 9, 396. [Google Scholar] [CrossRef] [Green Version]
  78. Ramos, I.; Stamatakis, K.; Oeste, C.L.; Pérez-Sala, D. Vimentin as a Multifaceted Player and Potential Therapeutic Target in Viral Infections. Int. J. Mol. Sci. 2020, 21, 4675. [Google Scholar] [CrossRef]
  79. Lee, L.K.; Bryant, K.J.; Bouveret, R.; Lei, P.W.; Duff, A.P.; Harrop, S.J.; Huang, E.P.; Harvey, R.P.; Gelb, M.H.; Gray, P.P.; et al. Selective Inhibition of Human Group IIA-Secreted Phospholipase A2 (HGIIA) Signaling Reveals Arachidonic Acid Metabolism Is Associated with Colocalization of HGIIA to Vimentin in Rheumatoid Synoviocytes. J. Biol. Chem. 2013, 288, 15269–15279. [Google Scholar] [CrossRef] [Green Version]
  80. Murakami, M.; Nakatani, Y.; Kuwata, H.; Kudo, I. Cellular Components That Functionally Interact with Signaling Phospholipase A2s. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2000, 1488, 159–166. [Google Scholar] [CrossRef]
  81. Bunimov, N.; Laneuville, O. Characterization of Proteins Associating with 5’ Terminus of PGHS-1 MRNA. Cell. Mol. Biol. Lett. 2010, 15, 196–214. [Google Scholar] [CrossRef] [PubMed]
  82. Dittmann, K.; Mayer, C.; Czemmel, S.; Huber, S.M.; Peter Rodemann, H. New Roles for Nuclear EGFR in Regulating the Stability and Translation of MRNAs Associated with VEGF Signaling. PLoS ONE 2017, 12, e0189087. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Lomonte, B.; Rangel, J. Snake Venom Lys49 Myotoxins: From Phospholipases A(2) to Non-Enzymatic Membrane Disruptors. Toxicon 2012, 60, 520–530. [Google Scholar] [CrossRef]
  84. Moreira, V.; Leiguez, E.; Janovits, P.M.; Maia-Marques, R.; Fernandes, C.M.; Teixeira, C. Inflammatory Effects of Bothrops Phospholipases A2: Mechanisms Involved in Biosynthesis of Lipid Mediators and Lipid Accumulation. Toxins 2021, 13, 868. [Google Scholar] [CrossRef] [PubMed]
  85. Tonello, F.; Simonato, M.; Aita, A.; Pizzo, P.; Fernández, J.; Lomonte, B.; Gutiérrez, J.M.M.; Montecucco, C. A Lys49-PLA2 Myotoxin of Bothrops Asper Triggers a Rapid Death of Macrophages That Involves Autocrine Purinergic Receptor Signaling. Cell Death Dis. 2012, 3, e343. [Google Scholar] [CrossRef] [Green Version]
  86. Spolaore, B.; Fernández, J.; Lomonte, B.; Massimino, M.L.; Tonello, F. Enzymatic Labelling of Snake Venom Phospholipase A. Toxicon 2019, 170, 99–107. [Google Scholar] [CrossRef] [PubMed]
  87. Dias, E.H.V.; Pereira, D.F.C.; de Sousa, B.B.; Matias, M.S.; de Queiroz, M.R.; Santiago, F.M.; Silva, A.C.A.; Dantas, N.O.; Santos-Filho, N.A.; de Oliveira, F. In Vitro Tracking of Phospholipase A2 from Snake Venom Conjugated with Magic-Sized Quantum Dots. Int. J. Biol. Macromol. 2019, 122, 461–468. [Google Scholar] [CrossRef] [PubMed]
  88. Sakane, F.; Hoshino, F.; Murakami, C. New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein. Int. J. Mol. Sci. 2020, 21, 6794. [Google Scholar] [CrossRef]
  89. Li, R.H.; Tian, T.; Ge, Q.W.; He, X.Y.; Shi, C.Y.; Li, J.H.; Zhang, Z.; Liu, F.Z.; Sang, L.J.; Yang, Z.Z.; et al. A Phosphatidic Acid-Binding LncRNA SNHG9 Facilitates LATS1 Liquid-Liquid Phase Separation to Promote Oncogenic YAP Signaling. Cell Res. 2021, 31, 1088–1105. [Google Scholar] [CrossRef] [PubMed]
  90. Quach, N.D.; Arnold, R.D.; Cummings, B.S. Secretory Phospholipase A2 Enzymes as Pharmacological Targets for Treatment of Disease. Biochem. Pharmacol. 2014, 90, 338–348. [Google Scholar] [CrossRef]
  91. Boija, A.; Klein, I.A.; Young, R.A. Biomolecular Condensates and Cancer. Cancer Cell 2021, 39, 174–192. [Google Scholar] [CrossRef]
  92. Patel, A.; Mitrea, D.; Namasivayam, V.; Murcko, M.A.; Wagner, M.; Klein, I.A. Principles and Functions of Condensate Modifying Drugs. Front. Mol. Biosci. 2022, 9, 1007744. [Google Scholar] [CrossRef] [PubMed]
  93. Tseng, A.; Inglis, A.S.; Scott, K.F. Native Peptide Inhibition. Specific Inhibition of Type II Phospholipases A2 by Synthetic Peptides Derived from the Primary Sequence. J. Biol. Chem. 1996, 271, 23992–23998. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Dolgin, E. Drug Startups Coalesce around Condensates. Nat. Biotechnol. 2021, 39, 123–125. [Google Scholar] [CrossRef] [PubMed]
Ijms 24 01579 g001 550
Figure 1. Structure of human sPLA2 of group X and sequence alignment of this with human sPLA2s of the groups IB, IIA, and V. The different sPLA groups are distinguished by the number and position of the disulphide bridges. In the sequence alignment, the conserved bridges in all conventional sPLA2s are shown in black, the active site residues in red, and the calcium binding loop residues in purple. Group X sPLA2s possess eight disulphide bridges, numbered from 1 to 8 according to the order of appearance in the sequence of the first cysteine in the bridge. Group I and group II sPLA2s possess seven bridges, whose cysteines are aligned with those of bridges 1–7 and 2–8 of group X sPLA2, respectively. In contrast, group V sPLA2s have six bridges, whose cysteines are aligned with those of bridges 2–7 of group X sPLA2. The three-dimensional structure representation was obtained from the protein data bank (PDB), file 1LE7, using the Cn3D macromolecular structure viewer.
Figure 1. Structure of human sPLA2 of group X and sequence alignment of this with human sPLA2s of the groups IB, IIA, and V. The different sPLA groups are distinguished by the number and position of the disulphide bridges. In the sequence alignment, the conserved bridges in all conventional sPLA2s are shown in black, the active site residues in red, and the calcium binding loop residues in purple. Group X sPLA2s possess eight disulphide bridges, numbered from 1 to 8 according to the order of appearance in the sequence of the first cysteine in the bridge. Group I and group II sPLA2s possess seven bridges, whose cysteines are aligned with those of bridges 1–7 and 2–8 of group X sPLA2, respectively. In contrast, group V sPLA2s have six bridges, whose cysteines are aligned with those of bridges 2–7 of group X sPLA2. The three-dimensional structure representation was obtained from the protein data bank (PDB), file 1LE7, using the Cn3D macromolecular structure viewer.
Ijms 24 01579 g001
Ijms 24 01579 g002 550
Figure 2. PTM sites and pathological genetic variants of human sPLA2s of group II. High throughput studies of PTMs identified, in these proteins, phosphorylation sites (in red), a ubiquitination site (in green), and a sumoylation site (in blue). Residues mutated in genetic diseases are evidenced in underlined bold. The asterisks indicate fully conserved residues, the colons conservation of amino acids with strong similar properties, while the symbol “.” indicates conservation of amino acids with weakly similar properties.
Figure 2. PTM sites and pathological genetic variants of human sPLA2s of group II. High throughput studies of PTMs identified, in these proteins, phosphorylation sites (in red), a ubiquitination site (in green), and a sumoylation site (in blue). Residues mutated in genetic diseases are evidenced in underlined bold. The asterisks indicate fully conserved residues, the colons conservation of amino acids with strong similar properties, while the symbol “.” indicates conservation of amino acids with weakly similar properties.
Ijms 24 01579 g002
Ijms 24 01579 g003 550
Figure 3. Group II phospholipase receptors or co-receptors have a direct physical interaction with each other, suggesting their involvement in multi-molecular complexes on the cell surface. Figure obtained via EsyN, using high and low throughput data from the Biogrid database [73]. The orange lines represent physical interaction between proteins.
Figure 3. Group II phospholipase receptors or co-receptors have a direct physical interaction with each other, suggesting their involvement in multi-molecular complexes on the cell surface. Figure obtained via EsyN, using high and low throughput data from the Biogrid database [73]. The orange lines represent physical interaction between proteins.
Ijms 24 01579 g003
Table
Table 1. Expression data and main diseases where conventional sPLA2s are involved.
Table 1. Expression data and main diseases where conventional sPLA2s are involved.
sPLA2 Group
Gene Name		Tissue Specificity *Single Cell Type
Specificity *		DiseasesRefs.
IB
PLA2G1B		Pancreas, lung, liver, colon, and kidney. At lower levels in ovary and testis, gastric mucosa, spleen, and brainExocrine glandular cells, pneumocytes,
neuronal cells,
plasma cells		Metabolic diseases
Behavior disorders
Arthritis rheumatoid
Spinal cord and brain injury
Cancer, mainly of lung, pancreas, liver, pituitary, colon, and adrenal glands		[6,7,8,9]
IIA
PLA2G2A		Liver, colon and small intestine, eyes, lung, pancreas, placenta, skeletal muscle, prostate, ovary, heart, kidney, synoviumExocrine glandular cells, adipocytes, epithelium cells, megakaryocyte–erythroid progenitor cells, chondrocytes, oocytes, granulocytesGut microbiota modulator
Arthritis rheumatoid
Atherosclerosis
Acute respiratory distress syndrome, Asthma
Coronary artery disease
Duchenne muscular dystrophy
Alzheimer’s disease
Spinal cord and brain injury
Cancer, mainly of prostate, colon, rectum, liver, breast, and skin		[6,10,11,12,13,14,15,16]
IID
PLA2G2D		Spleen and lymph nodes, pharynges, pancreas, lacrimal gland.
At lower levels in colon, thymus, placenta, small intestine, and prostate		Dendritic cells, macrophages,
plasma cells		Psoriasis
Infectious diseases
Cancer: breast, skin
Chronic obstructive pulmonary disease
Asthma		[17,18,19]
IIE
PLA2G2E		Adipose tissue, lacrimal gland, brain, heart, coronary artery, lung, placenta, and hair folliclesSmooth muscle cells, contractile cells, plasma cells, and melanocytesMetabolic diseases
Alopecia
Spinal cord injury
Ulcerative colitis
Chronic rhinosinusitis
Cancer: cutaneous melanoma, breast adenocarcinoma		[6,7,18]
IIF
PLA2G2F		Epidermis, placenta, testis, and thymus.
At lower levels in the heart, kidney, liver, and prostate		Keratinocytes,
plasma cells, osteoclast, astrocytes,
synovial cells, and
capillary endothelial cells		Psoriasis
Actinic keratosis
Arthritis rheumatoid
Cancer: myeloma, lymphoma, and skin		[18,20,21]
V
PLA2G5		Heart, retina, placenta, and adipose tissue.
At lower levels in lung		Sertoli cells, Leydig cells, cardiomyocytes, peritubular cells, cone photoreceptor cells, smooth muscle cells,
monocytes, and macrophages		Endometriosis
Osteoarthritis
Acute coronary syndrome
Late onset retinal degeneration
Familial benign flacked retina
Cancer: central nervous system, prostate		[7,22,23,24]
X
PLA2G10		Spleen, thymus, peripheral blood leukocytes, pancreas, lung, colon, neuronal fibers, white adipose tissue, and prostate Distal enterocytes, Paneth cells, intestinal goblet cells, exocrine glandular cells, gastric mucus-secreting cells, and pneumocytesAcute coronary syndrome
Cancer: colon-rectum, gastric, and esophagus		[25,26,27]
* Note: sPLA2s expression data are highly variable, as they depend on the condition, and state of activity and health, of the subject.
Table
Table 2. Main toxic effects caused by animal venom PLA2s, and number of proteins having that toxic property. Data were obtained through an advanced search in UniProtKB, selecting the protein family (phospholipase A2), the taxonomy (serpentes), and the keyword corresponding to the type of toxicity.
Table 2. Main toxic effects caused by animal venom PLA2s, and number of proteins having that toxic property. Data were obtained through an advanced search in UniProtKB, selecting the protein family (phospholipase A2), the taxonomy (serpentes), and the keyword corresponding to the type of toxicity.
Toxic EffectNumber of ProteinsDescriptionRefs.
EdemaGroup I: 4
Group II: 82		Local swelling that may appear within 15 min, spread, and become massive in two to three days and persist for up to three weeks[29]
Hemostasis impairingGroup I: 35
Group II: 66		Many venom PLA2s have anticoagulant activity, some by inhibition of coagulation factors (FXa, Factor VII), others by interfering with platelet aggregation. Platelet aggregation can be affected by reaction product of the phospholipase activity, however, not all PLA2s affect platelet aggregation, despite their common catalytic activity. Another possibility is the alteration of membrane receptors.[30,31]
MyotoxinsGroup I: 11
Group II: 81 1		The myotoxic activity of PLA2s can be local or systemic. Some myotoxins act only on muscle cells, and others have less specific activity and may be termed cytotoxins.[32]
NeurotoxinsGroup I: 38 2
Group II: 53 3		Venom neurotoxic PLA2s mostly act at the pre-synaptic level. Their specificity is thought to be due to interaction with membrane receptors. They cause paralysis by interfering with the release of acetyl choline.[33]
1 53 of 81 group II myotoxic PLA2 are enzymatically inactive homologues; 2 14 of 38 group I neurotoxic PLA2 are part of heterodimers or oligomers; 3 21 of 53 group II neurotoxic PLA2 are part of heterodimers or oligomers.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Tonello, F. Secretory Phospholipases A2, from Snakebite Envenoming to a Myriad of Inflammation Associated Human Diseases—What Is the Secret of Their Activity? Int. J. Mol. Sci. 2023, 24, 1579. https://doi.org/10.3390/ijms24021579

AMA Style

Tonello F. Secretory Phospholipases A2, from Snakebite Envenoming to a Myriad of Inflammation Associated Human Diseases—What Is the Secret of Their Activity? International Journal of Molecular Sciences. 2023; 24(2):1579. https://doi.org/10.3390/ijms24021579

Chicago/Turabian Style

Tonello, Fiorella. 2023. "Secretory Phospholipases A2, from Snakebite Envenoming to a Myriad of Inflammation Associated Human Diseases—What Is the Secret of Their Activity?" International Journal of Molecular Sciences 24, no. 2: 1579. https://doi.org/10.3390/ijms24021579

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop