| First Author | Fennell LM | Year | 2020 |
| Journal | EMBO J | Pages | e103303 |
| PubMed ID | 33215740 | Mgi Jnum | J:300149 |
| Mgi Id | MGI:6491818 | Doi | 10.15252/embj.2019103303 |
| Citation | Fennell LM, et al. (2020) Site-specific ubiquitination of the E3 ligase HOIP regulates apoptosis and immune signaling. EMBO J :e103303 |
| abstractText | HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), is a critical regulator of inflammation. However, how HOIP itself is regulated to control inflammatory responses is unclear. Here, we discover that site-specific ubiquitination of K784 within human HOIP promotes tumor necrosis factor (TNF)-induced inflammatory signaling. A HOIP K784R mutant is catalytically active but shows reduced induction of an NF-kappaB reporter relative to wild-type HOIP. HOIP K784 is evolutionarily conserved, equivalent to HOIP K778 in mice. We generated Hoip(K778R/K778R) knock-in mice, which show no overt developmental phenotypes; however, in response to TNF, Hoip(K778R/K778R) mouse embryonic fibroblasts display mildly suppressed NF-kappaB activation and increased apoptotic markers. On the other hand, HOIP K778R enhances the TNF-induced formation of TNFR complex II and an interaction between TNFR complex II and LUBAC. Loss of the LUBAC component SHARPIN leads to embryonic lethality in Hoip(K778R/K778R) mice, which is rescued by knockout of TNFR1. We propose that site-specific ubiquitination of HOIP regulates a LUBAC-dependent switch between survival and apoptosis in TNF signaling. |
