title: Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) activation requires phosphorylation of serine 412 by protein kinase A catalytic subunit α (PKACα) and X-linked protein kinase (PRKX).
abstract: TGF-β-activated kinase 1 (TAK1) is a key kinase in mediating Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) signaling. Although TAK1 activation involves the phosphorylation of Thr-184 and Thr-187 residues at the activation loop, the molecular mechanism underlying the complete activation of TAK1 remains elusive. In this work, we show that the Thr-187 phosphorylation of TAK1 is regulated by its C-terminal coiled-coil domain-mediated dimerization in an autophosphorylation manner. Importantly, we find that TAK1 activation in mediating downstream signaling requires an additional phosphorylation at Ser-412, which is critical for TAK1 response to proinflammatory stimuli, such as TNF-α, LPS, and IL-1β. In vitro kinase and shRNA-based knockdown assays reveal that TAK1 Ser-412 phosphorylation is regulated by cAMP-dependent protein kinase catalytic subunit α (PKACα) and X-linked protein kinase (PRKX), which is essential for proper signaling and proinflammatory cytokine induction by TLR/IL-1R activation. Morpholino-based in vivo knockdown and rescue studies show that the corresponding site Ser-391 in zebrafish TAK1 plays a conserved role in NF-κB activation. Collectively, our data unravel a previously unknown mechanism involving TAK1 phosphorylation mediated by PKACα and PRKX that contributes to innate immune signaling.
authors.affiliation: From the Life Sciences Institute and School of Medicine and Innovation Center for Cell Biology.
authors.forename: Chuan
authors.initials: C
authors.lastname: Ouyang
authors.affiliation: the College of Life Science, and.
authors.forename: Li
authors.initials: L
authors.lastname: Nie
authors.affiliation: the Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Meidi
authors.initials: M
authors.lastname: Gu
authors.affiliation: From the Life Sciences Institute and School of Medicine and Innovation Center for Cell Biology.
authors.forename: Ailing
authors.initials: A
authors.lastname: Wu
authors.affiliation: From the Life Sciences Institute and School of Medicine and Innovation Center for Cell Biology.
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.affiliation: the Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China wangxiaojian@cad.zju.edu.cn.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.affiliation: the College of Life Science, and shaojz@zju.edu.cn.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Shao
authors.affiliation: From the Life Sciences Institute and School of Medicine and Innovation Center for Cell Biology, xia2010@zju.edu.cn.
authors.forename: Zongping
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7
keywords: IL-1R; Inflammation; Innate Immunity; Mitogen-activated Protein Kinase (MAPK); NF-kappaB; Protein Kinase A (PKA); Serine/Threonine Protein Kinase; TAK1; Toll-like Receptor (TLR); Tumor Necrosis Factor (TNF)