Abstract
Chronic inflammation has been strongly associated with tumor progression, but the underlying mechanisms remain elusive. Here we demonstrate that E3 ligase Itch and deubiquitinase Cyld formed a complex via interaction through 'WW-PPXY' motifs. The Itch-Cyld complex sequentially cleaved Lys63-linked ubiquitin chains and catalyzed Lys48-linked ubiquitination on the kinase Tak1 to terminate inflammatory signaling via tumor necrosis factor. Reconstitution of wild-type Cyld but not the mutant Cyld(Y485A), which cannot associate with Itch, blocked sustained Tak1 activation and proinflammatory cytokine production by Cyld(-/-) bone marrow-derived macrophages. Deficiency in Itch or Cyld led to chronic production of tumor-promoting cytokines by tumor-associated macrophages and aggressive growth of lung carcinoma. Thus, we have identified an Itch-Cyld-mediated regulatory mechanism in innate inflammatory cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Binding Sites
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Cell Line, Transformed
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Cell Line, Tumor
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism*
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Deubiquitinating Enzyme CYLD
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Enzyme Activation / genetics
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HEK293 Cells
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Humans
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Inflammation / enzymology*
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Inflammation Mediators / metabolism
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MAP Kinase Kinase Kinases / metabolism*
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Molecular Sequence Data
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / mortality
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Neoplasms / pathology
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Protein Binding
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Sequence Alignment
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
Substances
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Inflammation Mediators
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Itch protein, mouse
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Ubiquitin-Protein Ligases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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CYLD protein, mouse
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Deubiquitinating Enzyme CYLD
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Cysteine Endopeptidases