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

Current models suggest that BAG6 and SGTA can each recognise a range of hydrophobic substrates located in the cytosol and direct them to an appropriate biosynthetic or degradative route. Hence, tail-anchored membrane proteins that follow a post-translational pathway for membrane insertion encounter both SGTA and the BAG6 complex prior to their TRC40-dependent integration at the ER (Leznicki et al., 2010; Mariappan et al., 2010; Mock et al., 2015). By contrast, the normal fate of hydrophobic substrates that are unable to translocate into or across the ER membrane is rapid, BAG6-facilitated, proteasomal degradation (Hessa et al., 2011; Rodrigo-Brenni et al., 2014; Wunderley et al., 2014). Both overexpression and knockdown studies indicate that SGTA antagonises the actions of the BAG6 complex to delay the proteasomal degradation of MLPs (Leznicki and High, 2012; Wunderley et al., 2014). Furthermore, the N-terminal domain of an SGTA homodimer can bind to the BAG6 complex through its two ubiquitin-like domain (UBL)-containing subunits, providing a physical link between these two quality control factors (Chartron et al., 2012; Darby et al., 2014; Leznicki et al., 2013; Xu et al., 2012). In the context of proteasomal degradation, BAG6 facilitates the RNF126-dependent ubiquitylation and proteasomal degradation of MLPs (Hessa et al., 2011; Rodrigo-Brenni et al., 2014), whereas SGTA acts to inhibit MLP degradation, most probably by favouring their deubiquitylation (Leznicki and High, 2012; Wunderley et al., 2014). In a physiological context it has been suggested that the SGTA-dependent antagonisation of BAG6 provides a rescue pathway for potentially viable substrates – such as tail-anchored proteins – that are prematurely ubiquitylated (Leznicki and High, 2012; Wunderley et al., 2014). Alternatively, cycles of substrate ubiquitylation and deubiquitylation might normally help to facilitate the selective degradation of MLPs (Brodsky, 2013; Zhang et al., 2013).