Pellino ubiquitinates hp-IRAK1

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).

IL1R/TLR诱导IRAK1发生Lys48-多泛素化及其随后的蛋白酶体降解。研究表明，IRAK1可经历Lys63连接的多泛素化，进而激活NFkB（Windheim等，2008；Conze等，2008）。对于蛋白质而言，这两种泛素化形式并非相互排斥（Newton K等，2008）。在刺激作用下，Lys63连接的泛素化可能首先发生以激活NFkB，但在较晚的时间，Lys48连接的泛素化发生，从而将蛋白质靶向蛋白酶体降解。IRAK1在Lys134和Lys180位点发生泛素化；这些位点的突变会损害IL1R介导的IRAK1泛素化（Conze等，2008）。一些作者提出TRAF6作为IRAK1 E3泛素连接酶的作用，但这一观点已被反驳（Windheim等，2008；Xiao等，2008）。目前普遍认为Pellino蛋白作为IRAK1 E3泛素连接酶发挥作用。Pellino1-3具备E3连接酶活性，并被认为能直接催化IRAK1的多泛素化（Xiao等，2008；Butler等，2007；Ordureau等，2008）。它们能够催化形成K63-和Lys48连接的多泛素链；连接类型受协同作用的E2酶控制。所有Pellino蛋白都能与E2异源二聚体UbcH13/Uev1a结合，催化Lys63连接的泛素化（Ordureau等，2008）。