IL1诱导IRAK1的多聚泛素化和降解。Pellino1-3具有E3连接酶活性，被认为可以直接催化IRAK1的多聚泛素化(Xiao et al. 2008;Butler等人2007;Ordureau等，2008)。它们能够催化形成K63-和k48连接的多聚泛素链;连锁的类型由E2酶控制。所有的Pellino蛋白都可以与E2异源二聚体UBE2N:UBE2V1 (Ubc13:Uev1a)结合，催化k63连接的泛素化(Ordureau et al. 2008)。IRAK1多聚泛素化最初被认为是通过蛋白酶体将IRAK1标记为蛋白质水解，但最近的研究表明涉及k63连接的多聚泛素化，而不是k48连接的多聚泛素化(Windheim et al. 2008;Conze et al. 2008)，被认为具有支架功能。IRAK1在K134和K180上被泛素化; mutation of these sites impairs IL1R-mediated ubiquitination 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). The current consensus is that Pellino proteins are the physiologically-relevant IRAK1 E3 ubiquitin ligases.