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 andfind 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.
Highlights
Tumor necrosis factor (TNF) is a pleiotropic cytokine implicated in an array of physiological processes, notably inflammation, cell survival, and cell death (Kalliolias and Ivashkiv, 2016)
The outcome of TNF signaling is tightly controlled by dynamic post-translational modifications (PTMs) of various substrates in the TNF receptor 1 (TNFR1) pathway, with proteolytic cleavage, phosphorylation, and ubiquitination playing significant roles (Annibaldi et al, 2018)
In response to TNF binding, TNFR1 trimerization triggers the assembly of a membrane-bound complex called complex I, consisting of TNFR1associated death domain (TRADD), TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis proteins 1/2, and receptor interacting protein kinase 1 (RIPK1). cIAP1/2-mediated ubiquitination of RIPK1 scaffolds the recruitment of the linear ubiquitin assembly complex (LUBAC), composed of HOIP, HOIL-1L and Sharpin, which in turn modifies RIPK1 and nuclear factor kB (NF-kB) essential modulator (NEMO) with linear ubiquitin (Met1-Ub) chains (Haas et al, 2009)
Summary
Tumor necrosis factor (TNF) is a pleiotropic cytokine implicated in an array of physiological processes, notably inflammation, cell survival, and cell death (Kalliolias and Ivashkiv, 2016). In response to TNF binding, TNFR1 trimerization triggers the assembly of a membrane-bound complex called complex I, consisting of TNFR1associated death domain (TRADD), TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis proteins 1/2 (cIAP1/2), and receptor interacting protein kinase 1 (RIPK1). Ubiquitinated RIPK1 within complex I recruits the TAK1/TAB2/TAB3 and IKK1/2/NEMO complexes, which promote mitogen-activated protein kinase (MAPK) and NF-kB activation and the transcription of several pro-survival and pro-inflammatory genes (Annibaldi et al, 2018). RIPK1 auto-phosphorylates on Ser-166 and assembles with RIPK3 into hetero-amyloid filaments (Mompean et al, 2018). This results in RIPK3 phosphorylation and phosphorylation of the necroptosis effector MLKL. RIPK1 ubiquitination is not limited to complex I, as it is ubiquitinated in the necrosome with both Met1- and Lys63-linked ubiquitin chains (Lys63-Ub), a ‘‘necroptotic ubiquitination’’ proposed to regulate its kinase activity and its interaction with RIPK3 within the complex (de Almagro et al, 2015, 2017; Wei et al, 2017; Dziedzic et al, 2018)
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