COP9 signalosome subunit 8 is essential for peripheral T cell homeostasis and antigen receptor–induced entry into the cell cycle from quiescence

Engagement of antigen receptors triggers the proliferation and functional activation of lymphocytes. Here we report that T cell homeostasis and antigen-induced responses require the COP9 signalosome (CSN), a regulator of the ubiquitin-proteasome system. Conditional deletion of the CSN subunit Csn8 in peripheral T lymphocytes disrupted formation of the CSN complex, reduced T cell survival and proliferation in vivo and impaired antigen-induced production of interleukin 2. Moreover, Csn8-deficient T cells showed defective entry into the cell cycle from the G0 quiescent state. This phenotype was associated with a lack of signal-induced expression of cell cycle–related genes, including G1 cyclins and cyclin-dependent kinases, and with excessive induction of p21Cip1. Our data define a CSN-dependent pathway of transcriptional control that is essential for antigen-induced initiation of T cell proliferation.

[1]  N. Wei,et al.  COP9: a new genetic locus involved in light-regulated development and gene expression in arabidopsis. , 1992, The Plant cell.

[2]  J. Sprent,et al.  Turnover of Naive-and Memory-phenotype T Cells , 1994 .

[3]  X. Deng,et al.  Characterization and Purification of the Mammalian COP9 Complex, a Conserved Nuclear Regulator Initially Identified as a Repressor of Photomorphogenesis in Higher Plants , 1998, Photochemistry and photobiology.

[4]  L. Leffet,et al.  Analysis of site-specific phosphorylation of the retinoblastoma protein during cell cycle progression. , 1999, Experimental Cell Research.

[5]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[6]  J. Kato,et al.  Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1 , 1999, Nature.

[7]  H. Gudmundsdottir,et al.  Dynamics and requirements of T cell clonal expansion in vivo at the single-cell level: effector function is linked to proliferative capacity. , 1999, Journal of immunology.

[8]  J. Sprent,et al.  Homeostatic T Cell Proliferation , 2000, The Journal of experimental medicine.

[9]  J. Borghans,et al.  T cell homeostasis: thymus regeneration and peripheral T cell restoration in mice with a reduced fraction of competent precursors. , 2001, The Journal of experimental medicine.

[10]  W. M. Weaver,et al.  A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. , 2001, Immunity.

[11]  A. Shevchenko,et al.  Promotion of NEDD8-CUL1 Conjugate Cleavage by COP9 Signalosome , 2001, Science.

[12]  C. Schwechheimer,et al.  Interactions of the COP9 Signalosome with the E3 Ubiquitin Ligase SCFTIR1 in Mediating Auxin Response , 2001, Science.

[13]  M. Eilers,et al.  Regulation of cyclin D2 gene expression by the Myc/Max/Mad network: Myc-dependent TRRAP recruitment and histone acetylation at the cyclin D2 promoter. , 2001, Genes & development.

[14]  Stephen C. Jameson,et al.  Maintaining the norm: T-cell homeostasis , 2002, Nature Reviews Immunology.

[15]  A. Carr,et al.  Deletion mutants in COP9/signalosome subunits in fission yeast Schizosaccharomyces pombe display distinct phenotypes. , 2002, Molecular biology of the cell.

[16]  M. Mannervik,et al.  COP9 signalosome subunits 4 and 5 regulate multiple pleiotropic pathways in Drosophila melanogaster. , 2002, Development.

[17]  Xiping Wang,et al.  The COP9 Signalosome Inhibits p27kip1 Degradation and Impedes G1-S Phase Progression via Deneddylation of SCF Cul1 , 2002, Current Biology.

[18]  L. Aravind,et al.  Role of Predicted Metalloprotease Motif of Jab1/Csn5 in Cleavage of Nedd8 from Cul1 , 2002, Science.

[19]  M. Seeger,et al.  The COP9 signalosome: at the interface between signal transduction and ubiquitin-dependent proteolysis. , 2002, Journal of cell science.

[20]  C. Schwechheimer,et al.  CSN1 N-terminal-dependent activity is required for Arabidopsis development but not for Rub1/Nedd8 deconjugation of cullins: a structure-function study of CSN1 subunit of COP9 signalosome. , 2002, Molecular biology of the cell.

[21]  Chen Dong,et al.  MAP kinases in the immune response. , 2002, Annual review of immunology.

[22]  K. Nakayama,et al.  The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. , 2003, Molecular cell.

[23]  Xing Wang Deng,et al.  The COP9 signalosome. , 2003, Annual review of cell and developmental biology.

[24]  T. Mak,et al.  From antigen to activation: specific signal transduction pathways linking antigen receptors to NF-kappaB. , 2003, Seminars in immunology.

[25]  M. Naumann,et al.  Fission yeast COP9/signalosome suppresses cullin activity through recruitment of the deubiquitylating enzyme Ubp12p. , 2003, Molecular cell.

[26]  K. A. Powell,et al.  Cop9/signalosome subunits and Pcu4 regulate ribonucleotide reductase by both checkpoint-dependent and -independent mechanisms. , 2003, Genes & development.

[27]  E. Lam,et al.  Commitment Point during G0→G1 That Controls Entry into the Cell Cycle , 2003, Molecular and Cellular Biology.

[28]  S. Kim,et al.  Skp2 regulates Myc protein stability and activity. , 2003, Molecular cell.

[29]  T. Jacks,et al.  Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry , 2003, Nature.

[30]  J. Lupski,et al.  COP9 Signalosome Subunit 3 Is Essential for Maintenance of Cell Proliferation in the Mouse Embryonic Epiblast , 2003, Molecular and Cellular Biology.

[31]  X. Deng,et al.  Disruption of the COP9 Signalosome Csn2 Subunit in Mice Causes Deficient Cell Proliferation, Accumulation of p53 and Cyclin E, and Early Embryonic Death , 2003, Molecular and Cellular Biology.

[32]  D. C. Dias,et al.  Nedd8 on cullin: building an expressway to protein destruction , 2004, Oncogene.

[33]  Shengjun Ren,et al.  Cyclin C/Cdk3 Promotes Rb-Dependent G0 Exit , 2004, Cell.

[34]  B. Clurman,et al.  The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[35]  K. Nakayama,et al.  Phosphorylation‐dependent degradation of c‐Myc is mediated by the F‐box protein Fbw7 , 2004, The EMBO journal.

[36]  S. Gerondakis,et al.  The mitogen-induced increase in T cell size involves PKC and NFAT activation of Rel/NF-kappaB-dependent c-myc expression. , 2004, Immunity.

[37]  S. Yamanaka,et al.  Multiple Functions of Jab1 Are Required for Early Embryonic Development and Growth Potential in Mice* , 2004, Journal of Biological Chemistry.

[38]  Yun-Cai Liu,et al.  Ubiquitin ligases and the immune response. , 2003, Annual review of immunology.

[39]  M. Kubota,et al.  Small Jab1‐containing subcomplex is regulated in an anchorage‐ and cell cycle‐dependent manner, which is abrogated by ras transformation , 2005, FEBS letters.

[40]  R. Deshaies,et al.  BMC Biochemistry BioMed Central , 2006 .

[41]  Y. Matsuo,et al.  The Jab1/COP9 signalosome subcomplex is a downstream mediator of Bcr-Abl kinase activity and facilitates cell-cycle progression. , 2005, Blood.

[42]  J. Kato,et al.  Myeloid leukemia factor 1 regulates p53 by suppressing COP1 via COP9 signalosome subunit 3 , 2005, The EMBO journal.

[43]  C. Dong,et al.  MAP kinases in immune responses. , 2005, Cellular & molecular immunology.

[44]  D. Cobrinik Pocket proteins and cell cycle control , 2005, Oncogene.

[45]  T. Fry,et al.  The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance , 2005, The Journal of Immunology.

[46]  Michele Pagano,et al.  S6K1- and ßTRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth , 2006, Science.

[47]  Jussi Taipale,et al.  Identification of pathways regulating cell size and cell-cycle progression by RNAi , 2006, Nature.

[48]  A. Wells,et al.  The role of cyclin-dependent kinases in T-cell development, proliferation, and function. , 2006, Critical reviews in immunology.

[49]  W. Tansey,et al.  The proteasome: a utility tool for transcription? , 2006, Current opinion in genetics & development.

[50]  Lars Rogge,et al.  The COP9 Signalosome Regulates Skp2 Levels and Proliferation of Human Cells* , 2006, Journal of Biological Chemistry.

[51]  A. Kimmel,et al.  The COP9 signalosome regulates cell proliferation of Dictyostelium discoideum. , 2006, European journal of cell biology.

[52]  N. Wei,et al.  Association of SAP130/SF3b-3 with Cullin-RING ubiquitin ligase complexes and its regulation by the COP9 signalosome , 2008, BMC Biochemistry.

[53]  M. Kitagawa,et al.  Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F‐1 after DNA damage , 2007, The EMBO journal.

[54]  D. Arnosti,et al.  Retinoblastoma protein regulation by the COP9 signalosome. , 2007, Molecular biology of the cell.

[55]  M. Seeger,et al.  Summary The COP 9 signalosome : at the interface between signal transduction and ubiquitin-dependent proteolysis , 2022 .