DOC_PUB_PIM_1

The PUB domain (IPR018997) occurs in some proteins linked to the regulation of ubiquitination. The first PUB domain characterised in PNGase was shown to bind the p97/VCP/TERA protein and remove oligosaccharide chains from misfolded proteins prior to degradation (Allen,2006; Zhao,2007). Next, the PUB domain HOIP/RNF31 protein (Q96EP0) was described to interact with the OTULIN deubiquitinating enzyme controlling the assembly of linear ubiquitination chains (Elliott,2014; Elliott,2016). The HOIP/RNF31 E3 ligase is a part of the linear ubiquitin chain assembly complex (LUBAC) composed of three core proteins: E3 ubiquitin ligases HOIP and HOIL-1, and SHARPIN. To date, HOIP/RNF31 is the only known E3 ubiquitin ligase that can generate linear (Met1-linked) ubiquitin chains on the target protein. These chains formed by the LUBAC complex play an important role in immune and inflammatory processes and programmed cell death. For example, the complex regulates NF-κB signalling in response to TNF activation by attaching ubiquitin chains to the target proteins. Conversely, both CYLD and OTULIN are known LUBAC deubiquitinases (DUBs) which eliminate the ubiquitin linkages and inhibit NF-κB activation (Dittmar,2019). The E3 ligase HOIP contains a PUB domain in the N-terminal part of the protein that directly binds proteins containing a PIM sequence (xD[LM]Yx). PUB-HOIP interacts with the deubiquitinase OTULIN (Q96BN8) via a PIM motif and through this interaction eliminates the linear ubiquitin linkages on the target protein protecting against cell death (Elliott,2014). Another DUB that cleaves the ubiquitin chains is CYLD (Q9NQC7). The mechanism of CYLD-HOIP interaction differs from OTULIN, as SPATA2 contains the PIM sequence which directly binds HOIP. Next, the PUB domain of SPATA2 recruits the USP domain of CYLD in a PIM motif independent manner, so SPATA2 serves as a bridge between CYLD and HOIP (Kupka,2016). Both OTULIN and CYLD DUBs, regulate the activity of the LUBAC-mediated linear ubiquitination by restricting the formation of ubiquitination chains on target proteins. The PUB domain of HOIP also recognises the PIM motif in p97/VCP (P55072; Schaeffer,2014). p97/VCP recruits HOIP to protein aggregates and together with other components of the LUBAC complex attaches linear ubiquitin chains to target proteins, promoting the removal of misfolded proteins thereby decreasing their toxic effect (van Well,2019). Phosphorylation of the tyrosine within the PIM sequence in OTULIN, SPATA2 and p97 proteins abolishes the interaction with HOIP. This PTM switch mechanism can modulate the poly-ubiquitination activity of the LUBAC complex, however, the regulation and dynamics of the phosphorylation remained uncharacterised when this entry was prepared.