Site-specific ubiquitination of the E3 ligase HOIP regulates apoptosis and immune signaling.
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.
Mesh Terms:
Animals, Apoptosis, Female, Gene Knock-In Techniques, HEK293 Cells, Humans, Male, Mice, NF-kappa B, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Signal Transduction, Transcriptome, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Animals, Apoptosis, Female, Gene Knock-In Techniques, HEK293 Cells, Humans, Male, Mice, NF-kappa B, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Signal Transduction, Transcriptome, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
EMBO J
Date: Dec. 15, 2019
PubMed ID: 33215740
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