Site-specific ubiquitination of the E3 ligase HOIP regulates apoptosis and immune signaling

ABSTRACT: 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-?B reporter relative to wild type HOIP. HOIP K784 is evolutionarily conserved, equivalent to HOIP K778 in mice. We generated HoipK778R/K778R knock in mice, which show no overt developmental phenotypes; however, in response to TNF, HoipK778R/K778R mouse embryonic fibroblasts display mildly suppressed NF-?B 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 HoipK778R/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.

SUBMITTER: Ms. Lilian, M Fennell 

PROVIDER: S-SCDT-EMBOJ-2019-103303 | biostudies-other |

REPOSITORIES: biostudies-other