p-Pellino-1,2,(3) p-Pellino:hp-IRAK1:TRAF6 K63-linked polyUb p-IRAK1:TRAF6 K63-polyubiquitin TRIKA1 Pellino ubiquitinates hp-IRAK1 Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 IL1R/TLR induces the Lys48- polyubiquitination and proteosomal degradation of IRAK1. IRAK1 has been shown to undergo Lys63-linked polyubiquitination which induced activation of NFkB (Windheim et al 2008; Conze et al 2008). These two forms of ubiquitination are not mutually exclusive for a protein (Newton K et al 2008). Upon stimulation Lys63-linked ubiquitination may occur first to activate NFkB, but at later time Lys48-linked ubiquitination occurs to target the proteins for proteosomal degradation.<p>IRAK1 is ubiquitinated on Lys134 and Lys180; 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 a 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 Lys48-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 Lys63-linked ubiquitylation (Ordureau et al 2008). Pubmed16884718 Pubmed17675297 Pubmed17997719 Pubmed18180283 Pubmed18326498 Pubmed18347055 Pubmed18724939 Pubmed19022706 Reactome Database ID Release 43937050 Reactome, http://www.reactome.org ReactomeREACT_24943 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 2