| First Author | Tokunaga F | Year | 2012 |
| Journal | EMBO J | Volume | 31 |
| Issue | 19 | Pages | 3856-70 |
| PubMed ID | 23032187 | Mgi Jnum | J:190394 |
| Mgi Id | MGI:5448785 | Doi | 10.1038/emboj.2012.241 |
| Citation | Tokunaga F, et al. (2012) Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-kappaB regulation. EMBO J 31(19):3856-70 |
| abstractText | 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. |
