Elsevier

Toxicon

Volume 44, Issue 5, October 2004, Pages 469-472
Toxicon

Mini-review
Ricin: the endoplasmic reticulum connection

https://doi.org/10.1016/j.toxicon.2004.07.002Get rights and content

Abstract

Ricin is a potent, plant‐derived, ribosome inactivating protein. To target ribosomes in the mammalian cytosol, ricin must firstly negotiate the endomembrane system of the cell to reach the endoplasmic reticulum. Here, the toxin is reduced and the catalytic A chain is recognised by ER components that facilitate its membrane translocation to the cytosol. To be toxic, ricin A chain must then avoid degradation, a conundrum made more tricky in that ubiquitination and proteasomal degradation are normally tightly coupled to the translocation process. This mini‐review summarieses current understanding of these events.

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.

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