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bioRxiv · 10.1101/742544

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

Fennell, L. M.·Deszcz, L.·Schleiffer, A.·Mechtler, K.·Kavirayani, A.·Ikeda, F.
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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 HOIP promotes Tumour Necrosis Factor (TNF)-induced inflammatory signalling by controlling TNF Receptor complex I (TNFR1) formation. A HOIP K784R mutant is catalytically active but shows reduced induction of an NF-{kappa}B reporter relative to wild type HOIP. HOIP K784 is evolutionarily conserved, equivalent to HOIP K778 in mice. We generated HoipK778R/K778R knockin mice, which show no overt developmental phenotypes; however, in response to TNF, HoipK778R/K778R mouse embryonic fibroblasts display suppressed NF-{kappa}B activation and increased sensitivity to apoptosis. 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-signalling.

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Fennell, L. M., Deszcz, L., Schleiffer, A., Mechtler, K., Kavirayani, A., Ikeda, F.. 2019-08-21. Site-specific ubiquitination of the E3 ligase HOIP regulates cell death and immune signaling. https://doi.org/10.1101/742544

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