Abstract
Ubiquitylation of the TNFR1 signalling complex (TNF-RSC) controls the activation of RIPK1, a kinase critically involved in mediating multiple TNFα-activated deleterious events. However, the molecular mechanism that coordinates different types of ubiquitylation modification to regulate the activation of RIPK1 kinase remains unclear. Here, we show that ABIN-1/NAF-1, a ubiquitin-binding protein, is recruited rapidly into TNF-RSC in a manner dependent on the Met1-ubiquitylating complex LUBAC to regulate the recruitment of A20 to control Lys63 deubiquitylation of RIPK1. ABIN-1 deficiency reduces the recruitment of A20 and licenses cells to die through necroptosis by promoting Lys63 ubiquitylation and activation of RIPK1 with TNFα stimulation under conditions that would otherwise exclusively activate apoptosis in wild-type cells. Inhibition of RIPK1 kinase and RIPK3 deficiency block the embryonic lethality of Abin-1 -/- mice. We propose that ABIN-1 provides a critical link between Met1 ubiquitylation mediated by the LUBAC complex and Lys63 deubiquitylation by phospho-A20 to modulate the activation of RIPK1.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics*
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Animals
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Apoptosis / genetics
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Autophagy-Related Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line, Transformed
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Fibroblasts / cytology
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Fibroblasts / metabolism*
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Gene Expression Regulation
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Genes, Lethal
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HEK293 Cells
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Signal Transduction
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Tumor Necrosis Factor alpha-Induced Protein 3 / genetics*
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Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Ubiquitination
Substances
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Adaptor Proteins, Signal Transducing
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Autophagy-Related Proteins
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Carrier Proteins
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Nerve Tissue Proteins
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Noxp70 protein, mouse
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Phosphoproteins
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Receptors, Tumor Necrosis Factor, Type I
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Tnfrsf1a protein, mouse
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Tnip2 protein, mouse
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Tumor Necrosis Factor-alpha
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk1 protein, mouse
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Ripk3 protein, mouse
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Tumor Necrosis Factor alpha-Induced Protein 3
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Tnfaip3 protein, mouse