Nonproteolytic functions of ubiquitin in cell signaling.

The small protein ubiquitin is a central regulator of a cell's life and death. Ubiquitin is best known for targeting protein destruction by the 26S proteasome. In the past few years, however, nonproteolytic functions of ubiquitin have been uncovered at a rapid pace. These functions include membrane trafficking, protein kinase activation, DNA repair, and chromatin dynamics. A common mechanism underlying these functions is that ubiquitin, or polyubiquitin chains, serves as a signal to recruit proteins harboring ubiquitin-binding domains, thereby bringing together ubiquitinated proteins and ubiquitin receptors to execute specific biological functions. Recent advances in understanding ubiquitination in protein kinase activation and DNA repair are discussed to illustrate the nonproteolytic functions of ubiquitin in cell signaling.

[1]  Zhijian J. Chen,et al.  The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. , 2004, Molecular cell.

[2]  Zhijian J. Chen,et al.  TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. , 2004, Molecular cell.

[3]  S. Ganesan,et al.  Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. , 2001, Molecular cell.

[4]  Y. Kadono,et al.  Segregation of TRAF6‐mediated signaling pathways clarifies its role in osteoclastogenesis , 2001, The EMBO journal.

[5]  Weidong Wang.  Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins , 2007, Nature Reviews Genetics.

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

[7]  M. Karin,et al.  Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. , 1999, Genes & development.

[8]  Osamu Takeuchi,et al.  TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity , 2007, Nature.

[9]  Shintaro Sato,et al.  HTLV-1 Tax-induced NFkappaB activation is independent of Lys-63-linked-type polyubiquitination. , 2007, Biochemical and biophysical research communications.

[10]  Matthew T Wheeler,et al.  The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses , 2004, Nature Immunology.

[11]  M. Kelliher,et al.  The Kinase Activity of Rip1 Is Not Required for Tumor Necrosis Factor-α-induced IκB Kinase or p38 MAP Kinase Activation or for the Ubiquitination of Rip1 by Traf2* , 2004, Journal of Biological Chemistry.

[12]  Shao-Cong Sun.  Deubiquitylation and regulation of the immune response , 2008, Nature Reviews Immunology.

[13]  S. Elledge,et al.  FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway , 2008, Nature Structural &Molecular Biology.

[14]  M. Kelliher,et al.  NOD2 Pathway Activation by MDP or Mycobacterium tuberculosis Infection Involves the Stable Polyubiquitination of Rip2* , 2007, Journal of Biological Chemistry.

[15]  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.

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

[17]  Boris Pfander,et al.  SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase , 2005, Nature.

[18]  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.

[19]  S. Akira,et al.  Involvement of the ubiquitin‐like domain of TBK1/IKK‐i kinases in regulation of IFN‐inducible genes , 2007, The EMBO journal.

[20]  K. Helin,et al.  The Ubiquitin Ligase HectH9 Regulates Transcriptional Activation by Myc and Is Essential for Tumor Cell Proliferation , 2005, Cell.

[21]  J. Tschopp,et al.  PIDD mediates NF-kappaB activation in response to DNA damage. , 2005, Cell.

[22]  Shao-Cong Sun,et al.  Retroviral oncoprotein Tax deregulates NF‐κB by activating Tak1 and mediating the physical association of Tak1–IKK , 2007, EMBO reports.

[23]  Bo Xu,et al.  Convergence of the Fanconi Anemia and Ataxia Telangiectasia Signaling Pathways , 2002, Cell.

[24]  G. Stark,et al.  Mutant Cells That Do Not Respond to Interleukin-1 (IL-1) Reveal a Novel Role for IL-1 Receptor-Associated Kinase , 1999, Molecular and Cellular Biology.

[25]  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.

[26]  J Wade Harper,et al.  The DNA damage response: ten years after. , 2007, Molecular cell.

[27]  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.

[28]  Seda Çöl Arslan,et al.  Malt1 ubiquitination triggers NF‐κB signaling upon T‐cell activation , 2007 .

[29]  S. Akira,et al.  The Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Requires the Ubiquitin-Conjugating Enzyme Ubc13 for NF-κB Activation , 2007, Journal of Virology.

[30]  J. Harper,et al.  DNA damage: ubiquitin marks the spot , 2008, Nature Structural &Molecular Biology.

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

[32]  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.

[33]  S. Elledge,et al.  Identification of the FANCI Protein, a Monoubiquitinated FANCD2 Paralog Required for DNA Repair , 2007, Cell.

[34]  J. Hurley,et al.  Ubiquitin-binding domains. , 2006, The Biochemical journal.

[35]  S. Miyamoto,et al.  PIASy mediates NEMO sumoylation and NF-κB activation in response to genotoxic stress , 2006, Nature Cell Biology.

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

[37]  Steven P Gygi,et al.  A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. , 2007, Molecular cell.

[38]  L. Cantley,et al.  Coordinated Regulation of Toll-Like Receptor and NOD2 Signaling by K63-Linked Polyubiquitin Chains , 2007, Molecular and Cellular Biology.

[39]  Xin Wang,et al.  A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination. , 2007, Molecular cell.

[40]  E. Kieff,et al.  Epstein–Barr virus latent membrane protein 1 activation of NF-κB through IRAK1 and TRAF6 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  K. J. Patel,et al.  The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair. , 2004, Molecular cell.

[42]  A. Pichlmair,et al.  Innate recognition of viruses. , 2007, Immunity.

[43]  R. Tibbetts,et al.  Molecular Linkage Between the Kinase ATM and NF-κB Signaling in Response to Genotoxic Stimuli , 2006, Science.

[44]  Anindya Dutta,et al.  UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. , 2006, Molecular cell.

[45]  C. Kim,et al.  STP-C, an oncoprotein of herpesvirus saimiri augments the activation of NF-kappaB through ubiquitination of TRAF6. , 2007, Journal of biochemistry and molecular biology.

[46]  J. Tschopp,et al.  PIDD Mediates NF-κB Activation in Response to DNA Damage , 2005, Cell.

[47]  P. Lambin,et al.  Lysine 63-Polyubiquitination Guards against Translesion Synthesis–Induced Mutations , 2006, PLoS genetics.

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

[49]  C. Scheidereit,et al.  A pervasive role of ubiquitin conjugation in activation and termination of IκB kinase pathways , 2005, EMBO reports.

[50]  W. Yeh,et al.  Ubiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF Signaling , 2007, Current Biology.

[51]  Zhijian J. Chen,et al.  TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[52]  D. Alessi,et al.  Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains. , 2008, The Biochemical journal.

[53]  T. Maniatis,et al.  A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways. , 1999, Genes & development.

[54]  Ivan Dikic,et al.  Atypical ubiquitin chains: new molecular signals , 2008, EMBO reports.

[55]  René Bernards,et al.  A Genomic and Functional Inventory of Deubiquitinating Enzymes , 2005, Cell.

[56]  K. Ishii,et al.  Cutting Edge: Pivotal Function of Ubc13 in Thymocyte TCR Signaling1 , 2006, The Journal of Immunology.

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

[58]  E. Pietras,et al.  A Deubiquitinase That Regulates Type I Interferon Production , 2007, Science.

[59]  A. Israël,et al.  Deciphering the pathway from the TCR to NF-κB , 2006, Cell Death and Differentiation.

[60]  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.

[61]  G. Courtois,et al.  Posttranslational modifications of NEMO and its partners in NF-κB signaling , 2006 .

[62]  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 .

[63]  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.

[64]  Xiaodong Wang,et al.  TNF-α Induces Two Distinct Caspase-8 Activation Pathways , 2008, Cell.

[65]  Alexander Varshavsky,et al.  The yeast DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme , 1987, Nature.

[66]  G. Dianov,et al.  Regulation of DNA repair by ubiquitylation , 2011, Biochemistry (Moscow).

[67]  C. Pickart,et al.  Noncanonical MMS2-Encoded Ubiquitin-Conjugating Enzyme Functions in Assembly of Novel Polyubiquitin Chains for DNA Repair , 1999, Cell.

[68]  John Calvin Reed,et al.  Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses , 2007, Proceedings of the National Academy of Sciences.

[69]  J. Inoue,et al.  Identification of TIFA as an Adapter Protein That Links Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) to Interleukin-1 (IL-1) Receptor-associated Kinase-1 (IRAK-1) in IL-1 Receptor Signaling* , 2003, The Journal of Biological Chemistry.

[70]  V. Dötsch,et al.  Ubiquitin binding mediates the NF-κB inhibitory potential of ABIN proteins , 2008, Oncogene.

[71]  E. Pietras,et al.  Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif , 2006, The EMBO journal.

[72]  G. Wider,et al.  Ubiquitin-Binding Domains in Y-Family Polymerases Regulate Translesion Synthesis , 2005, Science.

[73]  M. Foiani,et al.  SUMOylation regulates Rad18-mediated template switch , 2008, Nature.

[74]  A. Ashworth,et al.  Identification of the familial cylindromatosis tumour-suppressor gene , 2000, Nature Genetics.

[75]  S. Yamaoka,et al.  Activation of NF-κB by HTLV-I and implications for cell transformation , 2005, Oncogene.

[76]  Gabriel Núñez,et al.  Intracellular NOD-like receptors in host defense and disease. , 2007, Immunity.

[77]  Vrajesh V. Parekh,et al.  Cutting Edge: K63-Linked Polyubiquitination of NEMO Modulates TLR Signaling and Inflammation In Vivo1 , 2008, The Journal of Immunology.

[78]  M. Mann,et al.  Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6 , 2006, Nature.

[79]  Christine Yu,et al.  Ubiquitin Chain Editing Revealed by Polyubiquitin Linkage-Specific Antibodies , 2008, Cell.

[80]  S. Gygi,et al.  Regulation of monoubiquitinated PCNA by DUB autocleavage , 2006, Nature Cell Biology.

[81]  Boris Pfander,et al.  RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO , 2002, Nature.

[82]  Michael D. Schneider,et al.  The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function , 2006, Nature Immunology.

[83]  Zhijian J. Chen.  Ubiquitin signalling in the NF-κB pathway , 2005, Nature Cell Biology.

[84]  M. Rapé,et al.  Mechanism of Ubiquitin-Chain Formation by the Human Anaphase-Promoting Complex , 2008, Cell.

[85]  C. Bishop,et al.  A novel ubiquitin ligase is deficient in Fanconi anemia , 2003, Nature Genetics.

[86]  S. Miyamoto,et al.  Sequential Modification of NEMO/IKKγ by SUMO-1 and Ubiquitin Mediates NF-κB Activation by Genotoxic Stress , 2003, Cell.

[87]  H. Ruffner,et al.  Cancer-predisposing mutations within the RING domain of BRCA1: Loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[88]  Zhijian J. Chen,et al.  The TRAF 6 Ubiquitin Ligase and TAK 1 Kinase Mediate IKK Activation by BCL 10 and MALT 1 in T Lymphocytes , 2022 .

[89]  P. Lucas,et al.  A critical role of RICK/RIP2 polyubiquitination in Nod‐induced NF‐κB activation , 2008 .

[90]  T. Maniatis,et al.  Site-Specific Phosphorylation of IκBα by a Novel Ubiquitination-Dependent Protein Kinase Activity , 1996, Cell.

[91]  Avram Hershko,et al.  Ubiquitin: Roles in protein modification and breakdown , 1983, Cell.

[92]  A. Ashworth,et al.  The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. , 2008, Molecular cell.

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

[94]  E. Spiteri,et al.  FANCI is a second monoubiquitinated member of the Fanconi anemia pathway , 2007, Nature Structural &Molecular Biology.

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

[96]  Efterpi Papouli,et al.  Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. , 2005, Molecular cell.

[97]  L. Cantley,et al.  The Crohn's Disease Protein, NOD2, Requires RIP2 in Order to Induce Ubiquitinylation of a Novel Site on NEMO , 2004, Current Biology.

[98]  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.

[99]  A. Davies,et al.  Activation of Ubiquitin-Dependent DNA Damage Bypass Is Mediated by Replication Protein A , 2008, Molecular cell.

[100]  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.

[101]  J. Ashwell,et al.  NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-κB activation , 2008, Proceedings of the National Academy of Sciences.

[102]  P. Cohen,et al.  Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. , 2007, The Biochemical journal.

[103]  M. Babu,et al.  Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. , 2008, Molecular cell.

[104]  Seda Çöl Arslan,et al.  Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. , 2007, The EMBO journal.

[105]  A. Shahangian,et al.  Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response , 2006, Nature.

[106]  S. Akira,et al.  The human T-cell leukemia virus type 1 Tax oncoprotein requires the ubiquitin-conjugating enzyme Ubc13 for NF-kappaB activation. , 2007, Journal of virology.

[107]  Michael D. Schneider,et al.  Essential role of TAK1 in thymocyte development and activation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[108]  A. Israël,et al.  Deciphering the pathway from the TCR to NF-kappaB. , 2006, Cell death and differentiation.

[109]  K. Jeang,et al.  Inflammatory cardiac valvulitis in TAX1BP1‐deficient mice through selective NF‐κB activation , 2008, The EMBO journal.

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

[111]  A. D’Andrea,et al.  ATR couples FANCD2 monoubiquitination to the DNA-damage response. , 2004, Genes & development.

[112]  Elizabeth E. Molnar,et al.  TRAF6 Autoubiquitination-Independent Activation of the NFκB and MAPK Pathways in Response to IL-1 and RANKL , 2008, PloS one.

[113]  S. Yamaoka,et al.  Activation of NF-kappaB by HTLV-I and implications for cell transformation. , 2005, Oncogene.

[114]  René Bernards,et al.  The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. , 2005, Molecular cell.

[115]  Honglin Zhou,et al.  Bcl10 activates the NF-κB pathway through ubiquitination of NEMO , 2004, Nature.

[116]  S. Diebold.  Innate recognition of viruses. , 2010, Immunology letters.