Binding of SGTA to Rpn13 selectively modulates protein quality control

Leznicki, Pawel; Korac-Prlic, Jelena; Kliza, Katarzyna; Husnjak, Koraljka; Nyathi, Yvonne; Dikic, Ivan; High, Stephen

In addition to binding SGTA (this study), the C-terminal region of Rpn13 has also been shown to bind and activate UCH37 at the 19S proteasome (Bhattacharyya et al., 2014; Hamazaki et al., 2006; Yao et al., 2006). On this basis, we speculate that – following the arrival of MLPs at the proteasome – SGTA controls the access of these substrates to proteasome-associated DUBs (Fig. 7) and, thereby, influences MLP degradation (Wunderley et al., 2014), consistent with the effects on steady-state MLP levels that we observed in this study. Although we had previously suggested that proteasomal components are dispensable for the SGTA-mediated stabilisation of MLPs (Leznicki and High, 2012), it is now apparent that MLPs can be dealt with by alternate cellular quality control pathways that are – at least partially – redundant in nature (Rodrigo-Brenni et al., 2014). Interestingly, UCH37-mediated deubiquitylation can either suppress or promote polypeptide degradation in a substrate-specific manner (D'Arcy and Linder, 2012; Lee et al., 2011) and, hence, SGTA might impact on either of these potential fates for MLPs. We speculate that, in a physiological context, BAG6/SGTA-dependent cycles of substrate ubiquitylation and deubiquitylation are able to distinguish between aberrantly and correctly folded precursor proteins, thereby enhancing the fidelity of quality control (Brodsky, 2013; Wunderley et al., 2014; Zhang et al., 2013). Alternatively, SGTA binding and/or SGTA-facilitated deubiquitylation might provide a ‘rescue pathway’ for endogenous hydrophobic substrates, such as tail-anchored proteins, that might be prone to premature ubiquitylation (Ast et al., 2014; Leznicki and High, 2012; Wunderley et al., 2014). In the latter case it is noteworthy that, in addition to providing the binding site for Rpn13 (this study), the TPR domain of SGTA can also interact with Hsp70 and Hsp90 chaperones (Liou and Wang, 2005; Walczak et al., 2014), thereby providing substrates with potential access to additional quality control factors (cf. Fig. 7). Such a system would allow a putative BAG6/SGTA cycle to provide a proteasomal triage pathway, enabling aberrant precursors several attempts at productive folding/ER delivery before they are committed to degradation, and ensuring that the delivery of precursor proteins into competing pathways for maturation and degradation is carefully controlled (Fig. 7) (Leznicki and High, 2012; Wunderley et al., 2014).