title: The dual-specificity phosphatase DUSP14 negatively regulates tumor necrosis factor- and interleukin-1-induced nuclear factor-κB activation by dephosphorylating the protein kinase TAK1.
abstract: The transcription factor NF-κB is critically involved in the inflammatory response triggered by the proinflammatory cytokines TNF and IL-1. Various studies have demonstrated that activation of TAK1 (TGF-β-activated kinase 1) is an essential step in TNF- and IL-1-induced NF-κB activation pathways. In this study, we identified a member of the dual-specificity phosphatase family, DUSP14, as a negative regulator of TNF- and IL-1-triggered NF-κB activation by expression screens. We found that DUSP14 interacted with TAK1 and that this interaction was enhanced by TNF or IL-1 stimulation. Overexpression of DUSP14 dephosphorylated TAK1 at Thr-187, a residue in the activation loop critically involved in TAK1 activation. Knockdown of DUSP14 increased basal as well as TNF- and IL-1-induced TAK1 phosphorylation at Thr-187. Overexpression of DUSP14, but not its phosphatase-deficient mutant, inhibited TNF- and IL-1-induced as well as TAK1-mediated NF-κB activation, whereas knockdown of DUSP14 had opposite effects. These findings suggest that DUSP14 negatively regulates TNF- or IL-1-induced NF-κB activation by dephosphorylating TAK1 at Thr-187. Our study reveals a new post-translational regulatory mechanism of NF-κB activation triggered by the proinflammatory cytokines.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zheng
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Ran
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
mesh_terms: D002460:Cell Line; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D054637:Dual-Specificity Phosphatases; D007375:Interleukin-1; D020930:MAP Kinase Kinase Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C498843:DUSP14 protein, human