Abstract
ABSTRACTRpn13 is an intrinsic ubiquitin receptor of the 26S proteasome regulatory subunit that facilitates substrate capture prior to degradation. Here we show that the C-terminal region of Rpn13 binds to the tetratricopeptide repeat (TPR) domain of SGTA, a cytosolic factor implicated in the quality control of mislocalised membrane proteins (MLPs). The overexpression of SGTA results in a substantial increase in steady-state MLP levels, consistent with an effect on proteasomal degradation. However, this effect is strongly dependent upon the interaction of SGTA with the proteasomal component Rpn13. Hence, overexpression of the SGTA-binding region of Rpn13 or point mutations within the SGTA TPR domain both inhibit SGTA binding to the proteasome and substantially reduce MLP levels. These findings suggest that SGTA can regulate the access of MLPs to the proteolytic core of the proteasome, implying that a protein quality control cycle that involves SGTA and the BAG6 complex can operate at the 19S regulatory particle. We speculate that the binding of SGTA to Rpn13 enables specific polypeptides to escape proteasomal degradation and/or selectively modulates substrate degradation.
Highlights
The ubiquitin-proteasome system (UPS) constitutes a main pathway for protein degradation in eukaryotic cells, with polypeptides destined for disposal via this route bearing ubiquitin chains
These findings suggest that SGTA can regulate the access of MLPs to the proteolytic core of the proteasome, implying that a protein quality control cycle that involves SGTA and the BAG6 complex can operate at the 19S regulatory particle
This corresponds to the central tetratricopeptide repeat (TPR) domain of SGTA (Fig. 1B), a region previously implicated in binding both molecular chaperones and viral proteins (Dutta and Tan, 2008; Fielding et al, 2006; Liou and Wang, 2005; Walczak et al, 2014)
Summary
The ubiquitin-proteasome system (UPS) constitutes a main pathway for protein degradation in eukaryotic cells, with polypeptides destined for disposal via this route bearing ubiquitin chains. The selective and covalent attachment of the small ubiquitin polypeptide to these proteins is typically through lysine residues within the substrates and occurs through a cascade of sequential reactions catalysed by E1, E2 and E3 enzymes (Komander and Rape, 2012). Ubiquitin itself contains seven lysine residues, each of which can serve as acceptor sites during ubiquitylation, leading to the formation of polyubiquitin chains with different linkages. Protein ubiquitylation can be reversed by the action of proteases that are collectively known as deubiquitylating enzymes (DUBs) (Komander and Rape, 2012; Komander et al, 2009), and the removal of polyubiquitin by proteasomal DUBs precedes substrate degradation at the catalytic core (Bhattacharyya et al, 2014; Komander and Rape, 2012; Wauer and Komander, 2014)
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