Post-translational Modification of OTULIN Regulates Ubiquitin Dynamics and Cell Death

Cell Rep. 2019 Dec 10;29(11):3652-3663.e5. doi: 10.1016/j.celrep.2019.11.014. | PubMed

Todd Douglas¹, Maya Saleh²

1. Department of Microbiology and Immunology, McGill University, Montréal, QC H3G 0B1, Canada.
2. Department of Microbiology and Immunology, McGill University, Montréal, QC H3G 0B1, Canada; Department of Medicine, McGill University, Montréal, QC H3G 0B1, Canada. Electronic address: msaleh@immuconcept.org.

Abstract

Linear ubiquitination has emerged as an important post-translational modification that regulates NF-κB activation, inflammation, and cell death in both immune and non-immune compartments, including the skin. The deubiquitinase OTULIN specifically disassembles linear ubiquitin chains generated by the linear ubiquitin assembly complex (LUBAC) and is necessary to prevent embryonic lethality and autoinflammatory disease. Here, we dissect the direct role of OTULIN in cell death and find that OTULIN limits apoptosis and necroptosis in keratinocytes. During apoptosis, OTULIN is cleaved by capase-3 at Asp-31 into a C-terminal fragment that restricts caspase activation and cell death. During necroptosis, OTULIN is hyper-phosphorylated at Tyr-56, which modulates RIPK1 ubiquitin dynamics and promotes cell death. OTULIN Tyr-56 phosphorylation is counteracted by the activity of dual-specificity phosphatase 14 (DUSP14), which we identify as an OTULIN phosphatase that limits necroptosis. Our data provide evidence of dynamic post-translational modifications of OTULIN and highlight their importance in cell death outcome.

Presented By Todd Douglas