Mini-reviewRicin: the endoplasmic reticulum connection
Introduction
Ricin is a cytotoxic lectin produced in the seeds of the castor oil plant (Ricinus communis). The holotoxin contains a ribosome-inactivating A chain (RTA) disulphide linked to a galactose-binding lectin (RTB). Although infamous for its criminal potential, ricin has found widespread use as a research tool to study intracellular transport and ribosome inactivation, cell ablation and, when coupled to ligands that specifically target tumour cells or tumour vasculature, in cancer therapeutics. Here however, we focus primarily on our current understanding of the events and interactions occurring in and around the endoplasmic reticulum (ER) during ricin entry into mammalian cells.
Section snippets
Ricin reaches the ER of mammalian cells
RTB binds ricin to cell surface molecules containing exposed terminal galactose residues and can be internalised into most cell types by clathrin-dependent and clathrin-independent mechanisms (reviewed in Sandvig et al., 2002). These early endocytic pathways converge at endosomes from where a small but significant fraction of ricin reaches the Golgi for further retrograde transport to the ER. Although the amount of ricin reaching the ER is too low to permit detection by microscopy, there is
ER events
For RTA to act, it must be reductively cleaved from RTB to release a steric block of the active site. Such reduction may occur in the cytosol, although ER protein disulphide isomerase (PDI) has been implicated in reducing other toxins (cholera toxin (CT) and Pseudomonas exotoxin A). Expression of individual ricin subunits in the ER lumen of plant cells has revealed that the toxicity observed when glycosylated RTA is retro-translocated could be alleviated when RTA and RTB are co-expressed. In
Acknowledgements
We acknowledge funding from The Wellcome Trust, The UK BBSRC and Department of Health.
References (21)
- et al.
Ribosome-mediated folding of partially unfolded ricin A-chain
J. Biol. Chem.
(2000) - et al.
Ricin A chain can transport unfolded dihydrofolate reductase into the cytosol
J. Biol. Chem.
(1997) - et al.
Reductive activation of ricin and ricin A-chain immunotoxins by protein disulfide isomerase and thioredoxin reductase
Biochem. Pharmacol.
(2004) - et al.
An interaction between ricin and calreticulin that may have implications for toxin trafficking
J. Biol. Chem.
(2001) - et al.
Free ricin A chain, proricin, and native toxin have different cellular fates when expressed in tobacco protoplasts
J. Biol. Chem.
(1998) - et al.
Induction of direct endosome to endoplasmic reticulum transport in chinese hamster ovary (CHO) cells (LdlF) with a temperature-sensitive defect in {epsilon}-coatomer protein ({epsilon}-COP)
J. Biol. Chem.
(2003) - et al.
Pathways followed by protein toxins into cells
Int. J. Med. Microbiol.
(2004) - et al.
Protein disulfide isomerase acts as a redox-dependent chaperone to unfold cholera toxin
Cell
(2001) - et al.
Dependence of ricin toxicity on translocation of the toxin A-chain from the endoplasmic reticulum to the cytosol
J. Biol. Chem.
(1999) - et al.
Evidence that the transport of ricin to the cytoplasm is independent of both Rab6A and COPI
J. Cell Sci.
(2003)
Cited by (43)
Ricin toxin and its neutralizing antibodies: A review
2022, ToxiconCitation Excerpt :The RTA molecules that escape this process will be transported to the cytoplasm by the cell, and eventually inactivate ribosomes. So far, researchers have not yet come up with an answer to the intermediary used by RT molecules in reverse transport, but studies have shown that reverse transport inhibitors can significantly reduce the toxicity of RT (Roberts and Smith, 2004). Low-dose RT can induce cell apoptosis, cell membrane damage, membrane structure, function changes and cell inflammatory damage.
Advances in gold nanoparticles for optical detection of nerve agents
2022, Sensing of Deadly Toxic Chemical Warfare Agents, Nerve Agent Simulants, and their Toxicological AspectsGold nanoparticles as sensors in the colorimetric and fluorescence detection of chemical warfare agents
2016, Coordination Chemistry ReviewsAntibody treatment against pulmonary exposure to abrin confers significantly higher levels of protection than treatment against ricin intoxication
2015, Toxicology LettersCitation Excerpt :However, one should keep in mind that the catalytic activity, which resides in the A subunit of the toxin, is fully manifested only following the dissociation of its subunits (Tsai et al., 2002; Barbieri et al., 2004). In vivo, subunit dissociation occurs at a relatively late stage, after the holotoxin has entered the endoplasmic reticulum (Roberts and Smith, 2004) and does not determine the overall rate of intoxication. Rather, binding to the cell surface, entry and intracellular trafficking of ricin or abrin through the trans-Golgi and Golgi compartments to the ER, all of which precede subunit dissociation and enzymatic catalysis, comprise the rate-determining steps for in vivo ricin- and abrin-intoxication.
Physiological and molecular functions of the cytosolic peptide: N-glycanase
2015, Seminars in Cell and Developmental BiologyCitation Excerpt :At this moment, the ricin toxin A chain (RTA) and its derivatives are the only available ERAD substrates that have been clearly shown to be deglycosylated by Png1 in yeast [40,60,61]. Ricin is a very well known toxic lectin from Ricinus communis that is composed of a toxic A subunit (RTA) and a lectin B subunit [62,63]. A non-toxic mutant of RTA (RTAΔ), in which five amino acids critical for its toxicity had been deleted [60,64], was indeed shown to be degraded in a Png1-dependent manner, as evidenced by a delay in the degradation of RTA in png1Δ cells [40,61,65].