title: Lys48-linked TAK1 polyubiquitination at lysine-72 downregulates TNFα-induced NF-κB activation via mediating TAK1 degradation.
abstract: Protein kinases are important regulators of intracellular signal transduction pathways and play critical roles in diverse cellular processes. TAK1, a member of the MAPKKK family, is essential for TNFα-induced NF-κB activation. Phosphorylation and Lys(63)-linked polyubiquitination (polyUb) of TAK1 are critical for its activation. However, whether TAK1 is regulated by polyubiquitination-mediated protein degradation after its activation remains unknown. Here we report that TNFα induces TAK1 Lys(48) linked polyubiquitination and degradation at the later time course. Furthermore, we provide direct evidence that TAK1 is modified by Lys(48)-linked polyubiquitination at lysine-72 by mass spectrometry. A K72R point mutation on TAK1 abolishes TAK1 Lys(48)-linked polyubiquitination and enhances TAK1/TAB1 co-overexpression-induced NF-κB activation. As expected, TAK1 K72R mutation inhibits TNFα-induced Lys(48)-linked TAK1 polyubiquitination and degradation. TAK1 K72R mutant prolongs TNFα-induced NF-κB activation and enhances TNFα-induced IL-6 gene expression. Our findings demonstrate that TNFα induces Lys(48)-linked polyubiquitination of TAK1 at lysine-72 and this polyubiquitination-mediated TAK1 degradation plays a critical role in the downregulation of TNFα-induced NF-κB activation.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Liu
authors.forename: Renfang
authors.initials: R
authors.lastname: Mao
authors.forename: Lei
authors.initials: L
authors.lastname: An
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Fuchun
authors.initials: F
authors.lastname: Zhang
authors.forename: Guotong
authors.initials: G
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D025821:Polyubiquitin / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D025821:Polyubiquitin; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7