p-Pellino-1,2,(3) K63-polyubiquitin p-Pellino:hp-IRAK1:TRAF6 K63-linked poly-Ub-p-3S,3T-IRAK1:TRAF6 TRIKA1 Pellino ubiquitinates hp-IRAK1 upon TLR7/8 or 9 activation<br> Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 IL1 induces the poly-ubiquitination and degradation of IRAK1. This was believed to be K48-linked polyubiquitination, targeting IRAK1 for proteolysis by the proteasome, but recently IL-1R signaling has been shown to lead to K63-linked polyubiquitination of IRAK1 (Windheim et al. 2008; Conze et al. 2008), and demonstrated to have a role in the activation of NF-kappaB. IRAK1 is ubiquitinated on K134 and K180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al. 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al. 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. <br>Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13–Uev1a to catalyze K63-linked ubiquitylation (Ordureau et al. 2008). Pubmed16884718 Pubmed17675297 Pubmed17997719 Pubmed18180283 Pubmed18326498 Pubmed18347055 Pubmed19022706 Reactome Database ID Release 43975122 Reactome, http://www.reactome.org ReactomeREACT_24976 Reviewed: Gillespie, ME, 2010-10-29