3vux

Publication Abstract from PubMed

LUBAC (linear ubiquitin chain assembly complex) activates the canonical NF-kappaB pathway through linear polyubiquitination of NEMO (NF-kappaB essential modulator, also known as IKKgamma) and RIP1. However, the regulatory mechanism of LUBAC-mediated NF-kappaB activation remains elusive. Here, we show that A20 suppresses LUBAC-mediated NF-kappaB activation by binding linear polyubiquitin via the C-terminal seventh zinc finger (ZF7), whereas CYLD suppresses it through deubiquitinase (DUB) activity. We determined the crystal structures of A20 ZF7 in complex with linear diubiquitin at 1.70-1.98 A resolutions. The crystal structures revealed that A20 ZF7 simultaneously recognizes the Met1-linked proximal and distal ubiquitins, and that genetic mutations associated with B cell lymphomas map to the ubiquitin-binding sites. Our functional analysis indicated that the binding of A20 ZF7 to linear polyubiquitin contributes to the recruitment of A20 into a TNF receptor (TNFR) signalling complex containing LUBAC and IkappaB kinase (IKK), which results in NF-kappaB suppression. These findings provide new insight into the regulation of immune and inflammatory responses.

Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-kappaB regulation.,Tokunaga F, Nishimasu H, Ishitani R, Goto E, Noguchi T, Mio K, Kamei K, Ma A, Iwai K, Nureki O EMBO J. 2012 Oct 3;31(19):3856-70. doi: 10.1038/emboj.2012.241. Epub 2012 Aug 28. PMID:23032187^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.