Abstract
The heterodimeric plant toxin ricin binds exposed galactosyls at the cell surface of target mammalian cells, and, following endocytosis, is transported in vesicular carriers to the endoplasmic reticulum (ER). Subsequently, the cell-binding B chain (RTB) and the catalytic A chain (RTA) are separated reductively, RTA embeds in the ER membrane and then retrotranslocates (or dislocates) across this membrane. The protein conducting channels used by RTA are usually regarded as part of the ER-associated protein degradation system (ERAD) that removes misfolded proteins from the ER for destruction by the cytosolic proteasomes. However, unlike ERAD substrates, cytosolic RTA avoids destruction and folds into a catalytic conformation that inactivates its target ribosomes. Protein synthesis ceases, and subsequently the cells die apoptotically. This raises questions about how this protein avoids the pathways that are normally sanctioned for ER-dislocating substrates. In this review we focus on the molecular events that occur with non-tagged ricin and its isolated subunits at the ER–cytosol interface. This focus reveals that intra-membrane interactions of RTA may control its fate, an area that warrants further investigation.
Highlights
Ricin is a toxic heterodimeric protein expressed in the seeds of the castor oil plant Ricinus communis L., and comprises a cell binding B chain (RTB) disulfide-linked to a catalytic cytotoxic ribosome-inactivating protein (RTA, Figure 1)
There is no obvious role for caveolae [4] in productive intracellular routing and cytotoxicity does not appear to follow from recruitment of ricin to receptors in coated pits, since inhibiting coated pit formation by hypotonic shock [5] or by acidification of the cytosol [6] makes little difference, even though there is a 50% decrease in ricin endocytosis
We have suggested that membrane insertion may initiate retrotranslocation from the endoplasmic reticulum (ER), with RTA masquerading as a misfolded membrane protein that is removed to the cytosol by the ER quality control ER-associated protein degradation system (ERAD) (ER protein degradation) system [31]
Summary
Ricin is a toxic heterodimeric protein expressed in the seeds of the castor oil plant Ricinus communis L., and comprises a cell binding B chain (RTB) disulfide-linked to a catalytic cytotoxic ribosome-inactivating protein (RTA, Figure 1). TPST-dependent sulfation of RTA-sulf1- and RTA-sulf2-containing holotoxins in the Golgi would presumably only occur if the junction between the two chains is destabilised by sulf-tagging, or if the sulfation motifs extrude from the RTA:RTB interface: either implies structural remodeling of the holotoxin at the junction of the two toxin subunits. It follows that the details of retrograde trafficking and molecular interactions of RTA revealed by the use of holotoxins containing C-terminally tagged RTA may reflect features of the tagged RTA chain and not necessarily that of native toxin. In this review we focus on the molecular events that have been elucidated with non-modified ricin and its isolated subunits (or confirmed with non-modified toxin) and confine ourselves to examining events at the ER–cytosol interface
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