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Site‐specific ubiquitination of the E3 ligase HOIP regulates apoptosis and immune signaling
Author(s) -
Fennell Lilian M,
Gomez Diaz Carlos,
Deszcz Luiza,
Kavirayani Anoop,
Hoffmann David,
Yanagitani Kota,
Schleiffer Alexander,
Mechtler Karl,
Hagelkruys Astrid,
Penninger Josef,
Ikeda Fumiyo
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103303
Subject(s) - biology , ubiquitin ligase , ubiquitin , ubiquitin protein ligases , microbiology and biotechnology , signal transduction , immune system , dna ligase , signaling proteins , apoptosis , genetics , cancer research , dna , gene
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‐κB 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‐κB 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.