Met1-linked ubiquitination in immune signalling.
Bottom Line: N-terminal methionine-linked ubiquitin (Met1-Ub), or linear ubiquitin, has emerged as a central post-translational modification in innate immune signalling.These discoveries have significantly advanced our understanding of how nondegradative ubiquitin modifications control proinflammatory responses mediated by nuclear factor-κB and mitogen-activated protein kinases.In this review, we discuss the current data on Met1-Ub function and regulation, and point to some of the questions that still remain unanswered.
Affiliation: Department of Disease Biology, Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.Show MeSH
Mentions: Met1-Ub is produced by the genes UBB and UBC; in humans, these encode three and nine head-to-tail linked copies of Ub, respectively 10–12. The Met1-Ub molecules are processed cotranslationally by specialised deubiquitinases (DUBs) 13, providing free monomeric Ub for conjugation onto target proteins and for assembly into Lys-linked and Met1-linked Ub chains. The enzymatic assembly of Met1-Ub was first described by Iwai et al. in 2006, in a report identifying an approximately 600-kDa E3 complex containing the RING-in-between-RING proteins haem-oxidized IRP2 ubiquitin ligase-1 (HOIL-1; also termed RanBP-type and C3HC4-type zinc finger-containing 1 and RNF54) and HOIL-1-interacting protein (HOIP; also termed RNF31 and ZIBRA). The HOIP–HOIL-1 complex exclusively assembles Ub chains linked via Met1, and is termed the linear Ub chain assembly complex (LUBAC). Subsequently, SHANK-associated RH domain interactor (SHARPIN) was identified as a third core component of the LUBAC complex 14–16. HOIP is the catalytic subunit of the LUBAC complex, but is autoinhibited and requires binding of the HOIL-1 UBL domain to its Ub-associated (UBA) domain or the SHARPIN Ub-like (UBL) domain to its Npl4 zinc finger (NZF)2 domain for activity 14,17,18 (Fig. 1).
Affiliation: Department of Disease Biology, Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.