Abstract
Tumor necrosis factor alpha (TNF-α) plays a role in apoptosis and proliferation in multiple types of cells, and defects in TNF-α-induced apoptosis are associated with various autoimmune diseases. Here, we show that TRIM27, a tripartite motif (TRIM) protein containing RING finger, B-box, and coiled-coil domains, positively regulates TNF-α-induced apoptosis. Trim27-deficient mice are resistant to TNF-α-d-galactosamine-induced hepatocyte apoptosis. Trim27-deficient mouse embryonic fibroblasts (MEFs) are also resistant to TNF-α-cycloheximide-induced apoptosis. TRIM27 forms a complex with and ubiquitinates the ubiquitin-specific protease USP7, which deubiquitinates receptor-interacting protein 1 (RIP1), resulting in the positive regulation of TNF-α-induced apoptosis. Our findings indicate that the ubiquitination-deubiquitination cascade mediated by the TRIM27-USP7 complex plays an important role in TNF-α-induced apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Cycloheximide / pharmacology
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DNA-Binding Proteins / metabolism*
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Fibroblasts / physiology
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GTPase-Activating Proteins / metabolism
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HEK293 Cells
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Hep G2 Cells
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Hepatocytes / physiology
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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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Mitochondria / metabolism
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Nuclear Proteins / metabolism*
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Polyubiquitin / metabolism
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Protein Multimerization
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Protein Synthesis Inhibitors / pharmacology
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Protein Transport
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Tumor Necrosis Factor-alpha / physiology*
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Ubiquitin-Protein Ligases
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Ubiquitin-Specific Peptidase 7
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Ubiquitin-Specific Proteases / metabolism*
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Ubiquitination*
Substances
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DNA-Binding Proteins
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GTPase-Activating Proteins
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Nuclear Proteins
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Protein Synthesis Inhibitors
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Ralbp1 protein, mouse
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Tumor Necrosis Factor-alpha
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Polyubiquitin
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Cycloheximide
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Trim27 protein, mouse
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Ubiquitin-Protein Ligases
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Ubiquitin-Specific Peptidase 7
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Ubiquitin-Specific Proteases
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Usp7 protein, mouse