Site-specific ubiquitination of the E3 ligase HOIP regulates apoptosis and immune signaling.
Lilian M FennellCarlos Gomez-DiazLuiza DeszczAnoop KavirayaniDavid HoffmannKota YanagitaniAlexander SchleifferKarl MechtlerAstrid HagelkruysJosef M PenningerFumiyo IkedaPublished in: The EMBO journal (2020)
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 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-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 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.
Keyphrases
- wild type
- oxidative stress
- rheumatoid arthritis
- cell death
- diabetic rats
- transcription factor
- endothelial cells
- endoplasmic reticulum stress
- high fat diet induced
- signaling pathway
- high glucose
- cell cycle arrest
- type diabetes
- adipose tissue
- small molecule
- crispr cas
- cell proliferation
- metabolic syndrome
- drug induced
- skeletal muscle
- anti inflammatory
- extracellular matrix
- toll like receptor