Abstract
We have previously shown that tumor necrosis factor (TNF)-induced desumoylation and subsequent cytoplasmic translocation of HIPK1 are critical for ASK1-JNK activation. However, the mechanism by which TNF induces desumoylation of HIPK1 is unclear. Here, we show that SENP1, a SUMO-specific protease, specifically deconjugates SUMO from HIPK1 in vitro and in vivo. In resting endothelial cells (ECs), SENP1 is localized in the cytoplasm where it is complexed with an antioxidant protein thioredoxin. TNF induces the release of SENP1 from thioredoxin as well as nuclear translocation of SENP1. TNF-induced SENP1 nuclear translocation is specifically blocked by antioxidants such as N-acetyl-cysteine, suggesting that TNF-induced translocation of SENP1 is ROS dependent. TNF-induced nuclear import of SENP1 kinetically correlates with HIPK1 desumoylation and cytoplasmic translocation. Furthermore, the wild-type form of SENP1 enhances, whereas the catalytic-inactive mutant form or siRNA of SENP1 blocks, TNF-induced desumoylation and cytoplasmic translocation of HIPK1 as well as TNF-induced ASK1-JNK activation. More importantly, these critical functions of SENP1 in TNF signaling were further confirmed in mouse embryonic fibroblast cells derived from SENP1-knockout mice. We conclude that SENP1 mediates TNF-induced desumoylation and translocation of HIPK1, leading to an enhanced ASK1-dependent apoptosis.
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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Acetylcysteine / pharmacology
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Animals
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Antioxidants / pharmacology
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Apoptosis* / drug effects
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cattle
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Cells, Cultured
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Cysteine Endopeptidases
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Cytoplasm / metabolism
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Endopeptidases / genetics
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Endopeptidases / metabolism*
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology
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Endothelial Cells / metabolism*
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Endothelial Cells / pathology
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Humans
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MAP Kinase Kinase Kinase 5 / metabolism*
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Mice
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Mice, Knockout
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Mutation
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Processing, Post-Translational*
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Protein Serine-Threonine Kinases
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Protein Transport
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RNA Interference
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RNA, Small Interfering / metabolism
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Reactive Oxygen Species / metabolism
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Recombinant Proteins / metabolism
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Signal Transduction
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Small Ubiquitin-Related Modifier Proteins / metabolism*
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Thioredoxins / metabolism
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Time Factors
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Transfection
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Antioxidants
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Carrier Proteins
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RNA, Small Interfering
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Reactive Oxygen Species
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Recombinant Proteins
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Small Ubiquitin-Related Modifier Proteins
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Tumor Necrosis Factor-alpha
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Thioredoxins
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Protein Kinases
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Hipk1 protein, mouse
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Protein Serine-Threonine Kinases
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MAP Kinase Kinase Kinase 5
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MAP3K5 protein, human
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Endopeptidases
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SENP1 protein, human
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Cysteine Endopeptidases
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Senp1 protein, mouse
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Acetylcysteine