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

Substrate delivery to the proteasome is facilitated by both intrinsic (such as Rpn10 and Rpn13) (Husnjak et al., 2008; van Nocker et al., 1996) and shuttle (such as Rad23 and ubiquilins) ubiquitin receptors (Wang and Terpstra, 2013). Shuttle ubiquitin receptors bind ubiquitylated proteins through ubiquitin-associated domains (UBAs) and simultaneously interact with the proteasome through their ubiquitin-like domains (UBLs) (Wang and Terpstra, 2013). Rpn10 and Rpn13 interact with the UBLs of such shuttle factors, but can also bind directly to ubiquitylated substrates (Bhattacharyya et al., 2014; Husnjak and Dikic, 2012; Husnjak et al., 2008; van Nocker et al., 1996). It has been suggested that effective proteasomal degradation requires simultaneous recognition of the polyubiquitylated substrate by both the Rpn10 and Rpn13 subunits of the 19S regulatory particle (Bhattacharyya et al., 2014; Kang et al., 2006; Komander and Rape, 2012; Sakata et al., 2012). Substrates are subsequently deubiquitylated by Rpn11, a 19S-localised DUB, helping to maintain the cellular pool of free ubiquitin available for conjugation (Bhattacharyya et al., 2014; Komander and Rape, 2012; Komander et al., 2009; Wauer and Komander, 2014). Two additional DUBs, USP14 and UCHL5 (also known as and hereafter referred to as UCH37), also associate with the proteasome, although their precise roles are unclear (D'Arcy and Linder, 2012; Komander and Rape, 2012; Lee et al., 2011). Hence, whereas Rpn11 removes ubiquitin chains from proteasomal substrates en bloc USP14 and UCH37 seem to preferentially cleave off distal ubiquitin moieties, suggesting that they provide an editing or quality control function that can rescue inefficiently or prematurely ubiquitylated polypeptides (Bhattacharyya et al., 2014; D'Arcy and Linder, 2012; Lee et al., 2011). The recruitment of UCH37 to the proteasome is mediated by the C-terminal region of Rpn13, indicating that substrate recognition and ubiquitin-chain processing might be coupled (see D'Arcy and Linder, 2012; Komander et al., 2009 and references therein).