Lysine 63-linked Polyubiquitination of TAK1 at Lysine 158 Is Required for Tumor Necrosis Factor α- and Interleukin-1β-induced IKK/NF-κB and JNK/AP-1 Activation*

Transforming growth factor-β-activated kinase 1 (TAK1) plays an essential role in the tumor necrosis factor α (TNFα)- and interleukin-1β (IL-1β)-induced IκB kinase (IKK)/nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) activation. Here we report that TNFα and IL-1β induce Lys63-linked TAK1 polyubiquitination at the Lys158 residue within the kinase domain. Tumor necrosis factor receptor-associated factors 2 and 6 (TRAF2 and -6) act as the ubiquitin E3 ligases to mediate Lys63-linked TAK1 polyubiquitination at the Lys158 residue in vivo and in vitro. Lys63-linked TAK1 polyubiquitination at the Lys158 residue is required for TAK1-mediated IKK complex recruitment. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with TAK1 wild type or a TAK1 mutant containing a K158R mutation revealed the importance of this site in TNFα and IL-1β-mediated IKK/NF-κB and JNK/AP-1 activation as well as IL-6 gene expression. Our findings demonstrate that Lys63-linked polyubiquitination of TAK1 at Lys158 is essential for its own kinase activation and its ability to mediate its downstream signal transduction pathways in response to TNFα and IL-1β stimulation.

[1]  Lin-Feng Chen,et al.  Helicobacter pylori CagA activates NF‐κB by targeting TAK1 for TRAF6‐mediated Lys 63 ubiquitination , 2009, EMBO reports.

[2]  Songbin Fu,et al.  MEKK3 is required for lysophosphatidic acid-induced NF-kappaB activation. , 2009, Cellular signalling.

[3]  Zhijian J. Chen,et al.  Direct Activation of Protein Kinases by Unanchored Polyubiquitin Chains , 2009, Nature.

[4]  M. Dorf,et al.  PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination. , 2009, Molecular cell.

[5]  C. Heldin,et al.  The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner , 2008, Nature Cell Biology.

[6]  J. Shabanowitz,et al.  TAB4 Stimulates TAK1-TAB1 Phosphorylation and Binds Polyubiquitin to Direct Signaling to NF-κB* , 2008, Journal of Biological Chemistry.

[7]  Tomoaki Koga,et al.  Tumor Suppressor Cylindromatosis Acts as a Negative Regulator for Streptococcus pneumoniae-induced NFAT Signaling* , 2008, Journal of Biological Chemistry.

[8]  J. Ashwell,et al.  Lys63-Linked Polyubiquitination of IRAK-1 Is Required for Interleukin-1 Receptor- and Toll-Like Receptor-Mediated NF-κB Activation , 2008, Molecular and Cellular Biology.

[9]  P. Cohen,et al.  Interleukin-1 (IL-1) Induces the Lys63-Linked Polyubiquitination of IL-1 Receptor-Associated Kinase 1 To Facilitate NEMO Binding and the Activation of IκBα Kinase , 2008, Molecular and Cellular Biology.

[10]  L. Fitzpatrick,et al.  Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses , 2007, The Journal of experimental medicine.

[11]  Zhijian J. Chen,et al.  Ubiquitin-mediated activation of TAK1 and IKK , 2007, Oncogene.

[12]  Hao Wu,et al.  Site-specific Lys-63-linked Tumor Necrosis Factor Receptor-associated Factor 6 Auto-ubiquitination Is a Critical Determinant of IκB Kinase Activation* , 2006, Journal of Biological Chemistry.

[13]  P. Cohen,et al.  TAK1-binding protein 1 is a pseudophosphatase. , 2006, The Biochemical journal.

[14]  Michael Karin,et al.  Regulation and Function of IKK and IKK-Related Kinases , 2006, Science's STKE.

[15]  Kunihiro Matsumoto,et al.  The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL‐1 signalling pathway , 2006, EMBO reports.

[16]  Gabriel Pineda,et al.  Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. , 2006, Molecular cell.

[17]  S. Srinivasula,et al.  Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-κB activation , 2006, Nature Cell Biology.

[18]  Y. You,et al.  Ubiquitination of RIP Is Required for Tumor Necrosis Factor α-induced NF-κB Activation* , 2006, Journal of Biological Chemistry.

[19]  K. N. Pennington,et al.  Site-specific Monoubiquitination of IκB Kinase IKKβ Regulates Its Phosphorylation and Persistent Activation* , 2005, Journal of Biological Chemistry.

[20]  G. Cheetham,et al.  Structural basis for the interaction of TAK1 kinase with its activating protein TAB1. , 2005, Journal of molecular biology.

[21]  M. Arsura,et al.  X-linked Inhibitor of Apoptosis (XIAP) Inhibits c-Jun N-terminal Kinase 1 (JNK1) Activation by Transforming Growth Factor β1 (TGF-β1) through Ubiquitin-mediated Proteosomal Degradation of the TGF-β1-activated Kinase 1 (TAK1)* , 2005, Journal of Biological Chemistry.

[22]  Ki-Young Lee,et al.  TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. , 2005, Genes & development.

[23]  S. Akira,et al.  Essential function for the kinase TAK1 in innate and adaptive immune responses , 2005, Nature Immunology.

[24]  M. Karin,et al.  From JNK to Pay Dirt: Jun Kinases, their Biochemistry, Physiology and Clinical Importance , 2005, IUBMB life.

[25]  Sankar Ghosh,et al.  Signaling to NF-kappaB. , 2004, Genes & development.

[26]  P. Cohen,et al.  TAB3, a new binding partner of the protein kinase TAK1. , 2004, The Biochemical journal.

[27]  R. Gaynor,et al.  Role of the TAB2‐related protein TAB3 in IL‐1 and TNF signaling , 2003, The EMBO journal.

[28]  D. Morrison,et al.  Regulation of MAP kinase signaling modules by scaffold proteins in mammals. , 2003, Annual review of cell and developmental biology.

[29]  Y. Xiong,et al.  A Role for NF-κB Essential Modifier/IκB Kinase-γ (NEMO/IKKγ) Ubiquitination in the Activation of the IκB Kinase Complex by Tumor Necrosis Factor-α* , 2003, Journal of Biological Chemistry.

[30]  Y. Xiong,et al.  A role for NEMO/IKKγ Ubiquitination in the activation of the IκB kinase complex by TNF-α , 2003 .

[31]  Zhengfan Jiang,et al.  Interleukin-1 (IL-1) Receptor-Associated Kinase-Dependent IL-1-Induced Signaling Complexes Phosphorylate TAK1 and TAB2 at the Plasma Membrane and Activate TAK1 in the Cytosol , 2002, Molecular and Cellular Biology.

[32]  W. Arend.  The balance between IL-1 and IL-1Ra in disease. , 2002, Cytokine & growth factor reviews.

[33]  D. Goeddel,et al.  TNF-R1 Signaling: A Beautiful Pathway , 2002, Science.

[34]  Zhijian J. Chen,et al.  TAK1 is a ubiquitin-dependent kinase of MKK and IKK , 2001, Nature.

[35]  Zhijian J. Chen,et al.  Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain , 2000, Cell.

[36]  A. Dunne,et al.  The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense , 2000, Science's STKE.

[37]  K. Irie,et al.  TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. , 2000, Molecular cell.

[38]  T. Mak,et al.  Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. , 2000, Genes & development.

[39]  T. Deerinck,et al.  The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of Apoptosis , 1999, The Journal of experimental medicine.

[40]  D. Goeddel,et al.  Embryonic Lethality, Liver Degeneration, and Impaired NF-κB Activation in IKK-β-Deficient Mice , 1999 .

[41]  J. Ninomiya-Tsuji,et al.  The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway , 1999, Nature.

[42]  D. Goeddel,et al.  Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[43]  E. Zandi,et al.  AP-1 function and regulation. , 1997, Current opinion in cell biology.

[44]  R. Kind,et al.  The Nature of the 660-Kilometer Upper-Mantle Seismic Discontinuity from Precursors to the PP Phase , 1996, Science.

[45]  K. Irie,et al.  Identification of a Member of the MAPKKK Family as a Potential Mediator of TGF-β Signal Transduction , 1995, Science.

[46]  Songbin Fu,et al.  PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation. , 2009, Cellular signalling.

[47]  P. Cohen,et al.  The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1. , 2008, The Biochemical journal.

[48]  M. Karin,et al.  Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. , 2000, Annual review of immunology.

[49]  R. Davis,et al.  Signal transduction by the c-Jun N-terminal kinase. , 1999, Biochemical Society symposium.