TNFR1‐induced activation of the classical NF‐κB pathway

The molecular mechanisms underlying activation of the IκB kinase (IKK) complex are presumably best understood in the context of tumor necrosis factor (TNF) receptor‐1 (TNFR1) signaling. In fact, it seems that most, if not all, proteins relevant for this process have been identified and extensive biochemical and genetic data are available for the role of these factors in TNF‐induced IKK activation. There is evidence that protein modification–independent assembly of a core TNFR1 signaling complex containing TNFR1‐associated death domain, receptor interacting kinase 1, TNF receptor‐associated factor 2 and cellular inhibitor of apoptosis protein 1 and 2 starts a chain of nondegrading ubiquitination events that culminate in the recruitment and activation of IKK complex‐stimulating kinases and the IKK complex itself. Here, we sum up the known details of TNFR1‐induced IKK activation, address arising contradictions and discuss possible explanations resolving the apparent discrepancies.

[1]  R. Schwabe,et al.  IKKβ phosphorylates p65 at S468 in transactivaton domain 2 , 2005 .

[2]  M. Bertrand,et al.  cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. , 2008, Molecular cell.

[3]  R. Schwabe,et al.  IKKbeta phosphorylates p65 at S468 in transactivaton domain 2. , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  Juan F. García,et al.  Targeted Disruption of the ζPKC Gene Results in the Impairment of the NF-κB Pathway , 2001 .

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

[6]  David L. Vaux,et al.  IAP Antagonists Target cIAP1 to Induce TNFα-Dependent Apoptosis , 2007, Cell.

[7]  R. Korneluk,et al.  Inhibitor of Apoptosis Protein cIAP2 Is Essential for Lipopolysaccharide-Induced Macrophage Survival , 2006, Molecular and Cellular Biology.

[8]  Hao Wu,et al.  Structural basis for the lack of E2 interaction in the RING domain of TRAF2. , 2009, Biochemistry.

[9]  D. Kufe,et al.  MUC1 oncoprotein activates the IkappaB kinase beta complex and constitutive NF-kappaB signalling. , 2007, Nature cell biology.

[10]  Somasekar Seshagiri,et al.  De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling , 2004, Nature.

[11]  B. Seed,et al.  RIP mediates tumor necrosis factor receptor 1 activation of NF‐kappaB but not Fas/APO‐1‐initiated apoptosis. , 1996, The EMBO journal.

[12]  J. Waring,et al.  Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation , 2008, Proceedings of the National Academy of Sciences.

[13]  F. Chan,et al.  Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling. , 2007, Cytokine.

[14]  Erinna F. Lee,et al.  TRAF2 Must Bind to Cellular Inhibitors of Apoptosis for Tumor Necrosis Factor (TNF) to Efficiently Activate NF-κB and to Prevent TNF-induced Apoptosis , 2009, The Journal of Biological Chemistry.

[15]  J. Tschopp,et al.  Recruitment of TNF receptor 1 to lipid rafts is essential for TNFalpha-mediated NF-kappaB activation. , 2003, Immunity.

[16]  David Baltimore,et al.  Encoding NF-kappaB temporal control in response to TNF: distinct roles for the negative regulators IkappaBalpha and A20. , 2008, Genes & development.

[17]  Hana Kim,et al.  A fourth IkappaB protein within the NF-kappaB signaling module. , 2007, Cell.

[18]  S. Akira,et al.  Transforming Growth Factor β-activated Kinase 1 (TAK1) Kinase Adaptor, TAK1-binding Protein 2, Plays Dual Roles in TAK1 Signaling by Recruiting Both an Activator and an Inhibitor of TAK1 Kinase in Tumor Necrosis Factor Signaling Pathway* , 2009, The Journal of Biological Chemistry.

[19]  T. Mak,et al.  Activation of noncanonical NF-κB requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2, TRAF3 and the kinase NIK , 2008, Nature Immunology.

[20]  Jun Qin,et al.  Ubiquitin-specific Peptidase 21 Inhibits Tumor Necrosis Factor α-induced Nuclear Factor κB Activation via Binding to and Deubiquitinating Receptor-interacting Protein 1* , 2009, The Journal of Biological Chemistry.

[21]  K. Blackwell,et al.  The RING domain of TRAF2 plays an essential role in the inhibition of TNFalpha-induced cell death but not in the activation of NF-kappaB. , 2010, Journal of molecular biology.

[22]  Noula Shembade,et al.  Essential role for TAX1BP1 in the termination of TNF‐α‐, IL‐1‐ and LPS‐mediated NF‐κB and JNK signaling , 2007 .

[23]  S. Oshima,et al.  ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development , 2009, Nature.

[24]  P. Scheurich,et al.  Tumor necrosis factor signaling , 2003, Cell Death and Differentiation.

[25]  A. Kudo,et al.  TRAF2 Is Essential for TNF‐α‐Induced Osteoclastogenesis , 2004 .

[26]  W. Yeh,et al.  TRAF2 suppresses basal IKK activity in resting cells and TNFalpha can activate IKK in TRAF2 and TRAF5 double knockout cells. , 2009, Journal of molecular biology.

[27]  M. Lenardo,et al.  Competitive Control of Independent Programs of Tumor Necrosis Factor Receptor-Induced Cell Death by TRADD and RIP1 , 2006, Molecular and Cellular Biology.

[28]  S. Srinivasula,et al.  CARP-2 Is an Endosome-Associated Ubiquitin Ligase for RIP and Regulates TNF-Induced NF-κB Activation , 2008, Current Biology.

[29]  R. Gaynor,et al.  Histone H3 phosphorylation by IKK-α is critical for cytokine-induced gene expression , 2003, Nature.

[30]  J. Qin,et al.  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* , 2009, The Journal of Biological Chemistry.

[31]  E. Jung,et al.  TRAF6 deficiency promotes TNF-induced cell death through inactivation of GSK3β , 2008, Cell Death and Differentiation.

[32]  S. Ghosh,et al.  Shared Principles in NF-κB Signaling , 2008, Cell.

[33]  S. Akira,et al.  Involvement of linear polyubiquitylation of NEMO in NF-κB activation , 2009, Nature Cell Biology.

[34]  Hana Kim,et al.  A Fourth IκB Protein within the NF-κB Signaling Module , 2007, Cell.

[35]  J. Keats,et al.  Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling , 2008, Nature Immunology.

[36]  D. Goeddel,et al.  Posttranscriptional Downregulation of c-IAP2 by the Ubiquitin Protein Ligase c-IAP1 In Vivo , 2005, Molecular and Cellular Biology.

[37]  M. Kelliher,et al.  The kinase activity of Rip1 is not required for tumor necrosis factor-alpha-induced IkappaB kinase or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf2. , 2004, The Journal of biological chemistry.

[38]  Noula Shembade,et al.  The ubiquitin‐editing enzyme A20 requires RNF11 to downregulate NF‐κB signalling , 2009, The EMBO journal.

[39]  S. Westerheide,et al.  Tumor Necrosis Factor α-induced Phosphorylation of RelA/p65 on Ser529 Is Controlled by Casein Kinase II* , 2000, The Journal of Biological Chemistry.

[40]  Yongge Zhao,et al.  Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP. , 2007, Current biology : CB.

[41]  Christoph H Emmerich,et al.  Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. , 2009, Molecular cell.

[42]  George Kollias,et al.  Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses , 2008, Nature Immunology.

[43]  Douglas B. Evans,et al.  Mechanisms of proinflammatory cytokine-induced biphasic NF-kappaB activation. , 2003, Molecules and Cells.

[44]  H. Erdjument-Bromage,et al.  The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. , 1997, Cell.

[45]  A. Ting,et al.  RIP1 comes back to life as a cell death regulator in TNFR1 signaling , 2011, The FEBS journal.

[46]  Takahiro Doi,et al.  Tumor necrosis factor-alpha-induced IKK phosphorylation of NF-kappaB p65 on serine 536 is mediated through the TRAF2, TRAF5, and TAK1 signaling pathway. , 2003, The Journal of biological chemistry.

[47]  Zheng‐gang Liu,et al.  The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF-dependent Toll-like receptors , 2008, Nature Immunology.

[48]  T. Mak,et al.  Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors , 2008, Proceedings of the National Academy of Sciences.

[49]  W. Liao,et al.  The essential role of MEKK3 in TNF-induced NF-κB activation , 2001, Nature Immunology.

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

[51]  C. Scheidereit.  IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. , 2006, Oncogene.

[52]  M. Karin,et al.  The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF , 2001, Molecular and Cellular Biology.

[53]  R. Gaynor,et al.  Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. , 2003, Nature.

[54]  Yongge Zhao,et al.  Optineurin Negatively Regulates TNFα- Induced NF-κB Activation by Competing with NEMO for Ubiquitinated RIP , 2007, Current Biology.

[55]  A. Durán,et al.  Essential role of RelA Ser311 phosphorylation by ζPKC in NF‐κB transcriptional activation , 2003 .

[56]  S. Westerheide,et al.  Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. , 2000, The Journal of biological chemistry.

[57]  D. Vaux,et al.  RIPK1 is not essential for TNFR1-induced activation of NF-κB , 2010, Cell Death and Differentiation.

[58]  C. Shi,et al.  Tumor Necrosis Factor (TNF)-induced Germinal Center Kinase-related (GCKR) and Stress-activated Protein Kinase (SAPK) Activation Depends upon the E2/E3 Complex Ubc13-Uev1A/TNF Receptor-associated Factor 2 (TRAF2)* , 2003, The Journal of Biological Chemistry.

[59]  Z. Ronai,et al.  Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF‐κB , 2004, The EMBO journal.

[60]  Noula Shembade,et al.  Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling. , 2007, The EMBO journal.

[61]  Wafik S El-Deiry,et al.  Distinct Signaling Pathways in TRAIL- versus Tumor Necrosis Factor-Induced Apoptosis , 2006, Molecular and Cellular Biology.

[62]  M. Karin,et al.  The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF. , 2001, Molecular and cellular biology.

[63]  Hao Wu,et al.  Crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes: affinity, specificity, and regulation. , 2010, Molecular cell.

[64]  Zhijian J. Chen,et al.  A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFalpha and IL-1beta. , 2009, Molecular cell.

[65]  H. Erdjument-Bromage,et al.  The Transcriptional Activity of NF-κB Is Regulated by the IκB-Associated PKAc Subunit through a Cyclic AMP–Independent Mechanism , 1997, Cell.

[66]  A. Durán,et al.  Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation. , 2003, The EMBO journal.

[67]  P. Leder,et al.  The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. , 1998, Immunity.

[68]  M. Kelliher,et al.  The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. , 2000, Immunity.

[69]  Stefan Grimm,et al.  The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal , 1998 .

[70]  A. Durán,et al.  Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. , 2001, Molecular cell.

[71]  多田 久里守.  Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-κB activation and protection from cell death , 2002 .

[72]  M. Mayo,et al.  SMRT derepression by the IkappaB kinase alpha: a prerequisite to NF-kappaB transcription and survival. , 2004, Molecular cell.

[73]  D. Kufe,et al.  MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signalling , 2007, Nature Cell Biology.

[74]  Y. Azuma,et al.  TRAF5 Functions in Both RANKL‐ and TNFα‐Induced Osteoclastogenesis , 2003 .

[75]  Douglas B. Evans,et al.  Mechanisms of Proinflammatory Cytokine-Induced Biphasic NF-κB Activation. , 2003 .

[76]  C. Fearns,et al.  Triad3A Regulates Ubiquitination and Proteasomal Degradation of RIP1 following Disruption of Hsp90 Binding* , 2006, Journal of Biological Chemistry.

[77]  K. Ishii,et al.  Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling , 2006, Nature Immunology.

[78]  Vishva M Dixit,et al.  IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. , 2007, Cell.

[79]  Vinay Tergaonkar,et al.  IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. , 2007, Cell.

[80]  N. Copeland,et al.  The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20 , 2008, Nature Immunology.

[81]  B. Strahl,et al.  A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression. , 2003, Nature.

[82]  Young Chul Park,et al.  A Novel Mechanism of TRAF Signaling Revealed by Structural and Functional Analyses of the TRADD–TRAF2 Interaction , 2000, Cell.

[83]  A. Kudo,et al.  TRAF2 is essential for TNF-alpha-induced osteoclastogenesis. , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[84]  Cheng Luo,et al.  SPHINGOSINE-1-PHOSPHATE: A MISSING COFACTOR FOR THE E3 UBIQUITIN LIGASE TRAF2 , 2010, Nature.

[85]  D. Wallach.  Faculty Opinions recommendation of De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. , 2004 .

[86]  Yili Yang,et al.  TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2 , 2002, Nature.

[87]  J. Tschopp,et al.  Recruitment of TNF Receptor 1 to Lipid Rafts Is Essential for TNFα-Mediated NF-κB Activation , 2003 .

[88]  Takahiro Doi,et al.  Tumor Necrosis Factor-α-induced IKK Phosphorylation of NF-κB p65 on Serine 536 Is Mediated through the TRAF2, TRAF5, and TAK1 Signaling Pathway* , 2003, Journal of Biological Chemistry.

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

[90]  A. Ma,et al.  Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. , 2000, Science.

[91]  Sumit K. Chanda,et al.  Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression , 2010, Nature Cell Biology.

[92]  Kay Hofmann,et al.  Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain , 2009, Nature Structural &Molecular Biology.

[93]  Y. You,et al.  Ubiquitination of RIP is required for tumor necrosis factor alpha-induced NF-kappaB activation. , 2006, The Journal of biological chemistry.

[94]  S. Srinivasula,et al.  Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. , 2006, Nature cell biology.

[95]  W. Liao,et al.  The essential role of MEKK3 in TNF-induced NF-kappaB activation. , 2001, Nature immunology.

[96]  W. Fairbrother,et al.  c-IAP1 and c-IAP2 Are Critical Mediators of Tumor Necrosis Factor α (TNFα)-induced NF-κB Activation* , 2008, Journal of Biological Chemistry.

[97]  G. Haegeman,et al.  Transcriptional activation of the NF‐κB p65 subunit by mitogen‐ and stress‐activated protein kinase‐1 (MSK1) , 2003, The EMBO journal.