title: The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation.
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.
authors: Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors: Neesar
authors: N
authors: Ahmed
authors: Minghui
authors: M
authors: Zeng
authors: Indrajit
authors: I
authors: Sinha
authors: Lisa
authors: L
authors: Polin
authors: Wei-Zen
authors: WZ
authors: Wei
authors: Chozhavendan
authors: C
authors: Rathinam
authors: Richard
authors: R
authors: Flavell
authors: Ramin
authors: R
authors: Massoumi
authors: K
authors: K
authors: Venuprasad
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D018836:Inflammation Mediators / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011485:Protein Binding; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D018836:Inflammation Mediators; D020930:MAP Kinase Kinase Kinases; D044767:Ubiquitin-Protein Ligases; D000099151:MAP Kinase Kinase Kinase 7; C471637:Itch protein, mouse; C511601:CYLD protein, mouse