Li, Shuyu, Spooner, Robert A. , Allen, Stuart C. H., Guise, Christopher P., Ladds, Graham, Schnöder, Tina, Schmitt, Manfred J., Lord, Mike and Roberts, L. M. (Lynne M.) (2010) Folding-competent and folding-defective forms of Ricin A chain have different fates following retrotranslocation from the endoplasmic reticulum. Molecular Biology of the Cell, Vol.21 (No.15). pp. 2543-2554. doi:10.1091/mbc.E09-08-0743

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Abstract

We report that a toxic polypeptide retaining the potential to refold upon dislocation from the endoplasmic reticulum (ER)
to the cytosol (ricin A chain; RTA) and a misfolded version that cannot (termed RTAΔ), follow ER-associated degradation
(ERAD) pathways in Saccharomyces cerevisiae that substantially diverge in the cytosol. Both polypeptides are dislocated
in a step mediated by the transmembrane Hrd1p ubiquitin ligase complex and subsequently degraded. Canonical
polyubiquitylation is not a prerequisite for this interaction because a catalytically inactive Hrd1p E3 ubiquitin ligase
retains the ability to retrotranslocate RTA, and variants lacking one or both endogenous lysyl residues also require the
Hrd1p complex. In the case of native RTA, we established that dislocation also depends on other components of the
classical ERAD-L pathway as well as an ongoing ER–Golgi transport. However, the dislocation pathways deviate
strikingly upon entry into the cytosol. Here, the CDC48 complex is required only for RTAΔ, although the involvement of
individual ATPases (Rpt proteins) in the 19S regulatory particle (RP) of the proteasome, and the 20S catalytic chamber
itself, is very different for the two RTA variants. We conclude that cytosolic ERAD components, particularly the
proteasome RP, can discriminate between structural features of the same substrate.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Ricin, Endoplasmic reticulum, Translocation (Genetics), Saccharomyces cerevisiae, Cytosol
Journal or Publication Title:	Molecular Biology of the Cell
Publisher:	American Society for Cell Biology
ISSN:	1939-4586
Official Date:	1 August 2010
Dates:	Date Event 1 August 2010 Published
Volume:	Vol.21
Number:	No.15
Page Range:	pp. 2543-2554
DOI:	10.1091/mbc.E09-08-0743
Status:	Peer Reviewed
Access rights to Published version:	Restricted or Subscription Access
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Great Britain. Dept. of Health (DoH), Great Britain. Home Office, Wellcome Trust (London, England), Deutsche Forschungsgemeinschaft (DFG), National Institutes of Health (U.S.) (NIH)
Grant number:	080566/Z/06/Z (Wellcome), GRK845 (DFG), 5U01AI65869-02 (NIH)

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