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

Lilian M. Fennell, Carlos Gomez Diaz, Luiza Deszcz, Anoop Kavirayani, David Hoffmann, Kota Yanagitani, Alexander Schleiffer, Karl Mechtler, Astrid Hagelkruys, Josef Penninger, Fumiyo Ikeda

研究成果: ジャーナルへの寄稿学術誌査読

10 被引用数 (Scopus)


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.

ジャーナルEMBO Journal
出版ステータス出版済み - 12月 15 2020

!!!All Science Journal Classification (ASJC) codes

  • 神経科学一般
  • 分子生物学
  • 生化学、遺伝学、分子生物学一般
  • 免疫学および微生物学一般


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