Review
Role of the DNAJ/HSP40 family in the pathogenesis of insulin resistance and type 2 diabetes

https://doi.org/10.1016/j.arr.2021.101313Get rights and content

Highlights

  • Type 2 diabetes (T2D) is characterized by chronic hyperglycemia due to insulin resistance and β-cell dysfunction.

  • Impaired heat shock response (HSR) creates vulnerability to stress-induced adverse effects of insulin production/action.

  • In T2D, insufficient HSR leads to activation of pathways that abrogate insulin action and β-cell integrity and function.

  • Manipulating the HSR could represent an alternative approach to mitigate insulin resistance and β-cell dysfunction.

Abstract

Insulin resistance (IR) underpins a wide range of metabolic disorders including type 2 diabetes (T2D), metabolic syndrome and cardiovascular diseases. IR is characterized by a marked reduction in the magnitude and/or delayed onset of insulin to stimulate glucose disposal. This condition is due to defects in one or several intracellular intermediates of the insulin signaling cascade, ranging from insulin receptor substrate (IRS) inactivation to reduced glucose phosphorylation and oxidation. Genetic predisposition, as well as other precipitating factors such as aging, obesity, and sedentary lifestyles are among the risk factors underlying the pathogenesis of IR and its subsequent progression to T2D. One of the cardinal hallmarks of T2D is the impairment of the heat shock response (HSR). Human and animal studies provided compelling evidence of reduced expression of several components of the HSR (i.e. Heat shock proteins or HSPs) in diabetic samples in a manner that correlates with the degree of IR. Interventions that induce the HSR, irrespective of the means to achieve it, proved their effectiveness in enhancing insulin sensitivity and improving glycemic index. However, most of these studies have been focused on HSP70 family. In this review, we will focus on the novel role of DNAJ/HSP40 cochaperone family in metabolic diseases associated with IR.

Introduction

The incidence and prevalence of obesity and type 2 diabetes (T2D) are increasing sharply around the world, especially in countries favouring sedentary lifestyles associated with decreased physical activity and increased consumption of high-energy foods. According to the 2019 statistics from the International Diabetes Federation (www.idf.org), the worldwide estimation of the adult population (20–79 years old) with diabetes was 463 million (>95 % T2D) and diabetes is the fourth leading cause of mortality (Gregg et al., 2007). The IDF projected also a marked increase in disease incidence, reaching ∼700 million by 2040 if no proactive measures are taken to control and prevent this pandemic (IDF Diabetes Atlas 9th edition www.diabetesatlas.org). Poorly managed diabetes can lead to debilitating chronic conditions such as nephropathy, retinopathy, heart failure, limb amputation and stroke, that are difficult and costly to manage and burdens health care systems (Winocour, 2018).

T2D is a progressive metabolic disorder characterized by chronic hyperglycemia secondary to increased insulin resistance (IR) in peripheral organs combined with progressive failure of the pancreatic islet β-cells (Defronzo, 2009). The etiology is complex and involves an intricate interplay between genetic susceptibility, behavioral and environmental factors, including sedentary lifestyle, physical inactivity and obesity (DeFronzo et al., 2015). Obesity is a major independent risk factor for T2D through promotion of IR (Upadhyay et al., 2018).

Metabolic stress is a prominent hallmark underlying T2D through increased IR and β-cell dysfunction. It consists of a constellation of stress responses that are dysregulated in metabolically relevant sites such as skeletal muscle, adipose tissue, liver and pancreatic β-cells. This includes chronic inflammation referred to as metaflammation (Hotamisligil, 2017)), glucolipotoxicity (Poitout and Robertson, 2008), increased oxidative stress (Furukawa et al., 2004), defects in mitochondrial function or biogenesis (Szendroedi et al., 2011), and persistent endoplasmic reticulum (ER) stress (Hotamisligil, 2008). Impairment of the anti-inflammatory response (Pirola and Ferraz, 2017), anti-oxidant response system (Picu et al., 2017), and the heat shock response (HSR) (Abubaker et al., 2013; Abu-Farha et al., 2015; Hooper and Hooper, 2009), three crucial host anti-stress defense systems, are key events leading to IR and β-cell dysfunction.

This metabolically toxic environment leads to a loss of homeostatic signaling by activating several signaling pathways that abrogate insulin action in key insulin-responsive tissues (Hotamisligil, 2017). This includes the pathway that activates the c-Jun N-terminal stress kinase-1 (JNK1) (Hirosumi et al., 2002), the inhibitor of κB inflammatory kinase (IKKβ) (Cai et al., 2005), the mammalian target of rapamycin (mTOR) (Carlson et al., 2004),and the glycogen synthase kinase-3β (GSK-3β) (Dokken et al., 2005). Of these kinases, the role of JNK1 and IKKβ in metabolic stress-induced IR is well established and, as such, they emerged as attractive therapeutic targets for obesity-induced IR and T2D (Hirosumi et al., 2002). At the molecular level, both JNK1 and IKKβ are known to impair insulin action by phosphorylating, and thus inactivating, the insulin receptor substrates 1 and 2 (IRS-1 and IRS-2), and thereby converting them to poor substrates for the activated insulin receptor (Copps and White, 2012). Their roles in promoting genetic- or diet-induced obesity (DIO), metabolic inflammation, IR and β-cell dysfunction are validated by numerous studies using knockout, pharmacological inhibition and neutralization of inflammatory and stress pathways (Hirosumi et al., 2002; Vallerie and Hotamisligil, 2010). Impaired insulin action is also associated with an alteration in lipid metabolism, which leads to accumulation of an array of intracellular and circulating lipid metabolites such as diacylglycerol (DAG), ceramides, free fatty acids, triglycerides and oxidized cholesterol, that have adverse effects (Glass and Olefsky, 2012). They activate both JNK and IKKβ and thus further amplify the defect in insulin action (Boon et al., 2013).

In addition to insulin resistance, pancreatic β-cell failure due to increased β-cell apoptosis leading to deficit of β-cells plays a central role in the development of T2D (Butler et al., 2003). Emerging evidence from multiple lines of research has pointed to a role for metabolic stress in β-cell homeostasis and dysfunction (Swisa et al., 2017; Evans-Molina et al., 2013). It has been proposed that severe ER stress in beta cells, and the resulting cellular adaptation- namely the unfolded protein response (UPR), can reduce glucose-stimulated insulin secretion (Evans-Molina et al., 2013; Back and Kaufman, 2012). Given the ubiquity of the HSPs, it is unsurprising that some of these chaperone proteins have been implicated in β-cell dysfunction associated with T2D (Krause et al., 2014; Sharma et al., 2011) whilst, conversely, other studies have demonstrated that intra-cellular, as opposed to extra-cellular, HSPs are essential in protecting β-cells against damage. Elevated expression of intracellular HSP70 (iHSP70) in islets protected β-cells by reducing cytokine-induced cell death (Mokhtari et al., 2009). Liposomal delivery of iHSP70 into rat islets demonstrated its protective effect against IL-1β-induced impairment of pancreatic β-cell function (Margulis et al., 1991). Interestingly, human islet cells constitutively express higher levels of HSP70 and possess a higher antioxidant capacity than rodent islets, suggesting a possible explanation for the lower sensitivity of human β-cells to various toxins (Welsh et al., 1995). HSP70 also protects the pancreas against stress and prevents intracellular activation of trypsinogen in pancreatic acinar cells (Bhagat et al., 2000). Patients with diabetes have a reduced capacity to induce iHSP70 and HSF-1 in cells and tissues (Hooper and Hooper, 2005). Although iHSP70 has anti-inflammatory effects, when secreted into the extracellular environment (eHSP70), it exerts opposing effects, including inflammation and immune activation (De Maio, 2011). eHSP70 binds to cell receptors such as Toll-like receptor 2 (TLR2) and TLR4 in a variety of cells; chronic exposure of clonal rodent and human β-cells to eHSP70 can induce metabolic dysfunction and loss of cell integrity (Krause et al., 2014), suggesting a dual role of HSP70 in modulating pancreatic β-cell function in health and disease. HSP72 (HSPA1A) is also involved in modulating pancreatic β-cell survival and function. HSP72 prevented human islet amyloid polypeptide induced β-cell toxicity in T2D (Rosas et al., 2016). Recent studies have demonstrated that the glucagon like peptide-1 (GLP-1) analog, exendin-4, reduced lipotoxicity-induced ER stress and inflammation in pancreatic β-cells by modulating the expression of HSP72 (Madhu et al., 2020). However, as with HSP70, extracellular HSP72 (eHSP72) showed opposite effects on pancreatic β-cells. Elevated eHSP72 was positively correlated with insulin resistance in vivo and β-cell dysfunction in rodent islets and human β-cells (Krause et al., 2014). Other HSPs function as cytoprotectants in pancreatic β-cells by improving insulin secretory function; for example, constitutive overexpression of HSP27 protects islets from cytokine-induced injury (Dai et al., 2009). Moreover, HSPB1 was found to be a key pro-survival mediator against prolactin-induced oxidative stress in β-cells (Terra et al., 2019).

Living organisms cope with stressful insults by activating anti-stress response systems that enable them to maintain normal protein homeostasis “proteostasis”; a prerequisite to ensure a wide range of physiological functions vital for cell survival and tissue integrity (Morimoto, 2011). Any defect in those systems has adverse consequences for organismal health and lifespan. The heat shock response (HSR) is one sophisticated host defense system that allows cells to survive under various noxious conditions such as extreme temperatures, chemical, physical, environmental stresses as well as supra-physiological conditions (Jacob et al., 2017). This genetically programmed and universally conserved response is characterized by the prompt activation of one of the heat shock transcription factors (HSFs 1–4) (Gomez-Pastor et al., 2018), culminating in enhanced transcription of a battery of cytoprotective genes, the vast majority of which encode for heat shock proteins (HSPs) or molecular chaperones (Morimoto, 2011). In humans, HSF1 is the founding member of the HSF family, and is widely recognized as the master transcriptional regulator of the HSR (Morimoto, 2020). In addition to promoting the expression of genes encoding HSPs, HSF1 regulates the expression of an array of genes involved in cell survival, transport, signal transduction and metabolism (Akerfelt et al., 2010).

In most cells, HSF1 is constitutively expressed and predominantly kept in an inert state in the cytoplasm. Stress-dependent activation of HSF1 is accomplished through a highly regulated process involving multiple steps, transient protein-protein interactions, several stimulatory and inhibitory post-translational modifications, nuclear translocation, DNA-protein complex formation and transcriptional activation, response attenuation and degradation (Joutsen and Sistonen, 2019) (Fig. 1). Under normal conditions, HSF1 is sequestered as a monomer in the cytoplasm by physical interaction with other chaperones and cochaperones (HSP70, HSP40 and HSP90), forming an inactive heteroprotein complex (Gomez-Pastor et al., 2018). In response to stressful insults, HSF1 dissociates from this heteroprotein complex and undergoes a series of phosphorylation/dephosphorylation and oligomerization events, by which the active trimer is translocated to the nucleus where it transiently binds to the heat shock elements (HSREs), located at the promoter region of its downstream target genes, and stimulates their transcription (Morimoto, 2011). While in the nucleus, the persistent binding of HSF1 to its cognate DNA sequence and continuous expression of HSPs can be sustained by SIRT1 deacetylase (Westerheide et al., 2009). By contrast, mimicking the constitutive acetylation of HSF1 by mutating the conserved lysine acetylation residue (K80Q) facilitates its release from DNA and subsequent impairment of the HSR (Purwana et al., 2017). Similarly, the sumoylation of HSF1 on Lysine298 attenuates the HSF1-dependent transactivation property (Gomez-Pastor et al., 2018).

Acting as cellular guardians of the proteostasis network, HSPs participate in several key cellular functions under both physiological and stressful conditions, including suppression of protein aggregation, assisting the folding and stability of nascent and damaged proteins, translocation of proteins into cellular compartments and targeting irreversibly damaged proteins for degradation (Kampinga et al., 2019).

Recent evidence indicates HSPs’ involvement in binding and controlling the activity of several critical enzymes involved in inflammation, apoptosis, metabolism and cell signaling (Hooper and Hooper, 2009; Qi et al., 2012). Genetic manipulation of certain HSPs or modulation of their expression revealed their role in the pathogenesis of several chronic diseases including diabetes and neurological disorders (Urban et al., 2012; Zilaee and Shirali, 2016).

HSPs are broadly classified according to apparent molecular weight, amino acid sequence and function into distinct families. In humans, six major families of HSPs have been described; they consist of the small HSPs (HSPB), HSP40 (DNAJ), HSP60 (HSPD), HSP70 (HSPA), HSP90 (HSPC) and HSP110 (HSPH) (Kampinga et al., 2009). They were mostly known as molecular chaperones with a primary role to maintain proteostasis by binding to misfolded and/or damaged proteins and assisting in their proper folding, disaggregation and remodeling (Morimoto, 2011). Subsequently, their potent activities in blocking inflammation and apoptosis and improving insulin signaling and glucose homeostasis were recognized (Hooper and Hooper, 2009; Arredouani et al., 2019).

The role of the HSR in the pathogenesis of IR and T2D emerged from a study demonstrating reduced expression of HSP72 mRNA in skeletal muscle biopsies from T2D individuals that inversely correlated with severity of IR (Kurucz et al., 2002). Subsequent studies confirmed reduction of HSP72 protein in obese IR individuals (Bruce et al., 2003). Additionally, inducing expression of HSP72 in insulin-resistant individuals improved insulin sensitivity (Literati-Nagy et al., 2009). In streptozotocin-induced diabetes rat model, expression of HSP72 was impaired in skeletal muscle, confirming the human findings (Najemnikova et al., 2007). Mice lacking HSP72 are phenotypically obese and display glucose intolerance with increased IR in skeletal muscle (Drew et al., 2014). Pharmacological induction of HSP72 with BGP-15 in genetic (ob/ob) mice or genetic overexpression of HSP72 in skeletal muscle prevented diet-induced obesity (DIO)-driven IR (Chung et al., 2008).

Two other members of the HSR, HSP25/27 and HSP40/DNAJB3, were impaired in skeletal muscle of aged diabetic rats (Gupte et al., 1985) and adipose tissue of obese and T2D patients (Abubaker et al., 2013; Abu-Farha et al., 2015). A similar decrease in expression of mitochondrial HSP60 has been documented in brain of diabetic rats (Kleinridders et al., 2013). HSP25 expression was found to be adipose depot-specific following heat treatment, with greater expression in metabolically active white adipose tissue depots (i.e. visceral depots) compared with the subcutaneous adipose tissue (Rogers et al., 1985). Heat treatment also prevented high fat diet (HFD)-induced skeletal muscle insulin resistance in the rat through upregulation of HSP72 and HSP27 (Gupte et al., 2009). In healthy humans, lower expression of HSP72 protein in skeletal muscle was associated with increased adiposity and decreased insulin sensitivity (Henstridge et al., 2010). Therefore it is evident that HSP72 induction in skeletal muscle can alleviate obesity-induced insulin resistance via the mechanism of increasing fatty acid oxidation with consequent reduction in fat storage (Henstridge et al., 2010) and increasing mitochondrial number and oxidative capacity (Henstridge et al., 2014); hence, HSP72 induction can be considered as a potential therapeutic option for obesity and related metabolic syndromes. The beneficial effect of HSP72 in protecting HFD-induced insulin resistance was further demonstrated in a rat model with differing aerobic capacity. Heat-induced HSP72 induction was decreased after 3 days on HFD in low capacity runner (LCR) rats, whereas high capacity runner (HCR) rats were protected aginst HFD-induced metabolic conditions (Rogers et al., 2016). These findings strongly suggest that a decreased stress response, mediated by HSPs, can lead to an early and heightened susceptibility to metabolic insult in diet-induced obesity. Lastly, the activity of HSF1 is impaired in islets of a rat model of spontaneous T2D (Purwana et al., 2017), whereas overexpression of a constitutively active form of HSF1 in experimental rats with T2D enhanced insulin secretion by β-cells and improved glycemic index without causing hypoglycemia (Uchiyama et al., 2011). In addition, genetic ablation of HSP90, the natural inhibitor of HSF1, reversed IR and improved glucose tolerance in DIO mice (Jing et al., 2018).

IKKβ and JNK are serine/threonine kinases that provide critical molecular links between obesity, metabolic inflammation and insulin signaling (Hinz and Scheidereit, 2014). The activity of both is elevated in genetic and dietary models of obesity (Hirosumi et al., 2002), whereas animals lacking JNK1 and IKKβ are protected from DIO (Hirosumi et al., 2002). In diabetic patients, a mutation in JIP-1, a protein that physically interacts with JNK and regulates its activity, has been identified (Morel et al., 2010); JIP-1-deficient mice are protected from obesity-induced IR (Waeber et al., 2000). The pathophysiological roles of JNK1 and IKKβ in the etiology of IR and β-cell dysfunction have been confirmed by using pharmacological inhibitors (Negi and Sharma, 2015). Both enzymes are virtually activated by all forms of metabolic stress that contribute to IR and/or β-cell dysfunction such as pro-inflammatory cytokines, ROS, toxins, advanced glycation end products (AGEs), drugs, ER stress, free fatty acids and metabolic changes (Hirosumi et al., 2002). Their persistent activation leads to serine phosphorylation and inactivation of IRS-1/2 in insulin responsive sites and, thus, abrogation of insulin-mediated signal transduction (Werner et al., 2004). Consequently, these kinases became attractive targets for various metabolic abnormalities (Solinas and Becattini, 2017).

JNK is a member of the mitogen-activated protein kinase (MAPK) family that comprises JNK-1, JNK-2 and JNK-3 isoforms as well as various splicing variants (Solinas and Becattini, 2017). They regulate activities such as cell differentiation and proliferation, apoptosis, ROS accumulation, inflammation, metabolism and insulin signaling (Solinas and Becattini, 2017). Their biological functions are however isoform, cell-type and context dependent (Solinas and Karin, 2010). Activation of JNK triggers a series of transactivation events that converge to activate AP-1 (Jun/Fos) transcription factor (Weston and Davis, 2007). JNK is also involved in post-transcriptional control of gene expression by promoting mRNA stability (Chen et al., 1998).

IKKβ is another crucial enzyme that contributes to IR through at least two pathways (Gao et al., 2002). First, it contributes by directly phosphorylating and, thus, inactivating IRS-1/2 (Gao et al., 2002). Second, IKKβ is an upstream regulator of the inhibitor of NF-κB (IκB), whose role is to sequester NF-κB in an inactive form. Activation of IKKβ leads to phosphorylation, dissociation and degradation of IκB, allowing freed NF-κB complex to translocate to the nucleus and activate transcription of various inflammatory mediators such as TNF-α and IL-6 (Shoelson et al., 2003).

Since persistent activation of JNK1 and IKKβ kinases contribute to IR and, given the cytoprotective role of HSPs in preventing IR and improving metabolic deterioration involved in T2D, it has been postulated that HSPs act as negative regulators of JNK and IKKβ (Hooper and Hooper, 2009). In support of this, HSP72 abrogates the activity of JNK1 both in vitro and in vivo (Park et al., 2001). The direct interaction between HSP72 and JNK1 is however still controversial. Likewise, activity of IKKβ is abrogated by both HSP25 (Park et al., 2003), and HSP72 (Meldrum et al., 2003). On this basis, Hopper and Hooper proposed the “metabolic vicious cycle paradigm,” according to which T2D and the HSR are mutually exclusive (Fig. 2). In this cycle, metabolic stress leads to IR that contributes to impairment of the HSR and subsequent loss of cellular homeostasis (Hooper and Hooper, 2009). This cycle is accelerated by obesity and sedentary lifestyles; however, interventions that stimulate expression of HSPs mitigate it.

Collectively, these data emphasize the important role of the HSR in the pathogenesis of IR and T2D. The existence of an array of both non-pharmacological and pharmacological approaches to elicit this important host defense system makes it an ideal therapeutic pathway against metabolic diseases. This has been confirmed in subsequent studies showing that interventions that maintain or enhance the HSR (i.e., physical exercise, heat therapy, mild electrical therapy, pharmacological inducers and genetic overexpression) improve clinical outcomes both in humans and experimental animals (Literati-Nagy et al., 2009; Chung et al., 2008; Kondo et al., 2011).

Section snippets

Human DNAJ proteins

The DNAJ/HSP40 cochaperone is the largest and most diverse family of the HSPs. DNAJ proteins (J-proteins) are obligate components of the HSP70 chaperoning cycle as they both stimulate the ATPase activity of HSP70 and play a critical role in client substrate selection, loading onto HSP70 and keeping the bound substrates in successive refolding cycles (Tiwari et al., 2013). Some members of the DNAJ family may have chaperoning activity independent of HSP70 (Ajit Tamadaddi and Sahi, 2016). In

Conclusion

Despite the tremendous effort devoted to combatting IR and T2D, the disease still remains a major worldwide health concern affecting all the age groups. Preventing the disease and identifying high risk individuals is the best strategy to constrain the epidemic spread of the disease and its progression to chronic complications. Changes in lifestyle habits (healthy dietary intake, increased physical activity and a reduction of sedentariness) are effective tools in high risk individuals.

Author contributions

Conception and design: A.D., H.A., N.K., A.S.M, A.E.B. and M.D. Drafting the article A.D., M.D. Review and editing: A.E.B. MD is the guarantor of this work.

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgements

We are indebted to the group of scientific community working on the role of HSR in the pathogenesis of metabolic diseases associated with IR for shedding light on the importance of manipulating this crucial host defense to fight against this devastating disease. We did our best to cite all the relevant references and we apologize for any missed work. This study was supported by an intramural grant from Qatar Biomedical Research Institute/Hamad Bin Khalifa University to MD.

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