Pellino ubiquitinates hp-IRAK1

Stable Identifier
Reaction [transition]
Homo sapiens
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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.

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.
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).

Literature References
PubMed ID Title Journal Year
18724939 Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies

Kirkpatrick, DS, Dugger, D, Lam, C, Fellouse, FA, Kelley, RF, Bosanac, I, Komuves, L, French, DM, Dixit, VM, Ferrando, RE, Gordon, N, Yu, C, Lill, JR, Newton, K, Hymowitz, SG, Compaan, D, Wertz, IE, Tan, J, Sidhu, SS, Matsumoto, ML

Cell 2008
18347055 Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation

Conze, DB, Landstrom, A, Ashwell, JD, Thomas, JA, Wu, CJ

Mol Cell Biol 2008
17675297 Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases

Hanly, JA, Butler, MP, Moynagh, PN

J Biol Chem 2007
17997719 The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1

Peggie, M, Ordureau, A, Carrick, E, Morrice, N, Windheim, M, Smith, H, Cohen, P

Biochem J 2008
Catalyst Activity

ubiquitin-ubiquitin ligase activity of p-Pellino:hp-IRAK1:TRAF6 [plasma membrane]

Orthologous Events
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