A well-defined co-translational pathway couples the synthesis and translocation of nascent polypeptides into and across the membrane of the endoplasmic reticulum (ER), thereby minimizing the possibility of the hydrophobic signals and transmembrane domains that such proteins contain from being exposed to the cytosol. Nevertheless, a proportion of these co-translational substrates may fail to reach the ER, and therefore mislocalize to the cytosol where their intrinsic hydrophobicity makes them aggregation-prone. A range of hydrophobic precursor proteins that employ alternative, post-translational, routes for ER translocation also contribute to the cytosolic pool of mislocalized proteins (MLPs). In this review, we detail how mammalian cells can efficiently deal with these MLPs by selectively targeting them for proteasomal degradation. Strikingly, this pathway for MLP degradation is regulated by cytosolic components that also facilitate the TRC40-dependent, post-translational, delivery of tail-anchored membrane proteins (TA proteins) to the ER. Among these components are small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) and Bcl-2-associated athanogene 6 (BAG6), which appear to play a decisive role in enforcing quality control over hydrophobic precursor proteins that have mislocalized to the cytosol, directing them to either productive membrane insertion or selective ubiquitination and proteasomal degradation.
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June 2016
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Cover Image
Cover Image
Shining a spotlight on outer membrane protein folding. Outer membrane proteins (OMPs) [such as OmpA (green, top left)] have to navigate their way from the ribosome (bottom of image) via trigger factor (red) and SecB (turquoise), through the SecYEG translocon (red/yellow) in the inner membrane (IM). They are then chaperoned across the periplasm until they can insert and fold into their ultimate destination, the outer membrane. For further details see pp. 802–809. The figure was produced by Jim Horne. - PDF Icon PDF LinkTable of Contents
Review Article|
June 09 2016
On the road to nowhere: cross-talk between post-translational protein targeting and cytosolic quality control
Joseph Casson;
Joseph Casson
*Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, U.K.
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Michael McKenna;
Michael McKenna
*Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, U.K.
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Stephen High
Stephen High
1
*Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, U.K.
1To whom correspondence should be addressed (email stephen.high@manchester.ac.uk).
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Publisher: Portland Press Ltd
Received:
February 01 2016
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem Soc Trans (2016) 44 (3): 796–801.
Article history
Received:
February 01 2016
Citation
Joseph Casson, Michael McKenna, Stephen High; On the road to nowhere: cross-talk between post-translational protein targeting and cytosolic quality control. Biochem Soc Trans 15 June 2016; 44 (3): 796–801. doi: https://doi.org/10.1042/BST20160045
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