Crossref journal-article
Oxford University Press (OUP)
The Journal of Immunology (286)
Abstract

Abstract Protein inhibitors of activated STATs (PIAS) represent a small family of nuclear proteins that modulate the activity of many transcription factors and act as E3 ligases for covalent modification of proteins with the small ubiquitin-like modifier (SUMO). In particular, PIASy has been shown to inhibit the activation of gene expression by the IFN-responsive transcription factor STAT1 and the Wnt-responsive transcription factor LEF1. To assess the function of PIASy in vivo, we generated and analyzed mice carrying a targeted mutation of the Piasy gene. We find that homozygous mutant mice have no obvious morphological defects and have a normal distribution of lymphocyte populations. Molecular analysis of signaling in response to IFN-γ and Wnt agonists revealed a modest reduction in the activation of endogenous and transfected target genes. Two-dimensional analysis of total proteins and SUMO-modified proteins in transformed pre-B cells showed no significant differences between wild-type mice and homozygous mutant mice. Taken together, our data indicate that PIASy has a modest effect on cytokine and Wnt signaling, suggesting a redundancy with other members of the family of PIAS proteins.

Bibliography

Roth, W., Sustmann, C., Kieslinger, M., Gilmozzi, A., Irmer, D., Kremmer, E., Turck, C., & Grosschedl, R. (2004). PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling. The Journal of Immunology, 173(10), 6189–6199.

Authors 8
  1. Wera Roth (first)
  2. Claudio Sustmann (additional)
  3. Matthias Kieslinger (additional)
  4. Andrea Gilmozzi (additional)
  5. Denis Irmer (additional)
  6. Elisabeth Kremmer (additional)
  7. Chris Turck (additional)
  8. Rudolf Grosschedl (additional)
References 76 Referenced 72
  1. Chung, C. D., J. Liao, B. Liu, X. Rao, P. Jay, P. Berta, K. Shuai. 1997. Specific inhibition of Stat3 signal transduction by PIAS3. Science 278:1803. (10.1126/science.278.5344.1803)
  2. Liu, B., J. Liao, X. Rao, S. A. Kushner, C. D. Chung, D. D. Chang, K. Shuai. 1998. Inhibition of Stat1-mediated gene activation by PIAS1. Proc. Natl. Acad. Sci. USA 95:10626. (10.1073/pnas.95.18.10626)
  3. Sachdev, S., L. Bruhn, H. Sieber, A. Pichler, F. Melchior, R. Grosschedl. 2001. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15:3088. (10.1101/gad.944801)
  4. Yamamoto, H., M. Ihara, Y. Matsuura, A. Kikuchi. 2003. Sumoylation is involved in β-catenin-dependent activation of Tcf-4. EMBO J. 22:2047. (10.1093/emboj/cdg204)
  5. Arora, T., B. Liu, H. He, J. Kim, T. L. Murphy, R. L. Modlin, K. Shuai. 2003. PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. J. Biol. Chem. 278:21327. (10.1074/jbc.C300119200)
  6. Tanaguchi, T., A. Takaoka. 2001. A weak signal for strong responses: IFN-α/β revisited. Nat. Rev. Mol. Cell Biol. 2:378. (10.1038/35073080)
  7. Levy, D. E., J. E. Darnell, Jr. 2002. STATs: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 3:651. (10.1038/nrm909)
  8. Darnell, J. E., Jr, I. M. Kerr, G. R. Stark. 1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415. (10.1126/science.8197455)
  9. Ihle, J. N., B. A. Witthuhn, F. W. Quelle, K. Yamamoto, W. E. Thierfelder, B. Kreider, O. Silvennoinen. 1994. Signaling by the cytokine receptor superfamily, JAKs and STATS. Trends Biochem. Sci. 19:222. (10.1016/0968-0004(94)90026-4)
  10. van Noort, M., H. Clevers. 2002. TCF transcription factors, mediators of Wnt-signaling in development and cancer. Dev. Biol. 244:1. (10.1006/dbio.2001.0566)
  11. Rodriguez, M. S., J. M. P. Desterro, S. Lain, C. A. Midgley, D. P. Lane, R. T. Hay. 1999. SUMO-1 modification activates the transcriptional response of p53. EMBO J. 18:6455. (10.1093/emboj/18.22.6455)
  12. Kotaja, N., S. Aittomäki, O. Silvennoinen, J. J. Palvimo, O. A. Jänne. 2000. ARIP3 (androgen receptor-interacting protein 3) and other PIAS (protein inhibitor of activated STAT) proteins differ in their ability to modulate steroid receptor-dependent transcriptional activation. Mol. Endocrinol. 14:1986. (10.1210/mend.14.12.0569)
  13. Rödel, B., K. Tavassoli, H. Karsunky, T. Schmidt, M. Bachmann, F. Schaper, P. Heinrich, K. Shuai, H. P. Elsässer, T. Möröy. 2000. The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3. EMBO J. 19:5845. (10.1093/emboj/19.21.5845)
  14. Johnson, E. S., A. A. Gupta. 2001. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106:735. (10.1016/S0092-8674(01)00491-3)
  15. Kahyo, T., T. Nishida, H. Yasuda. 2001. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol. Cell 8:713. (10.1016/S1097-2765(01)00349-5)
  16. Takahashi, Y., T. Kahyo, A. Toh-e, H. Yasuda, Y. Kikuchi. 2001. Yeast Ull1/Siz1 is a novel SUMO1/Smt3 ligase for septin components and functions as an adaptor between conjugating enzyme and substrates. J. Biol. Chem. 276:48973. (10.1074/jbc.M109295200)
  17. Zentner, M. D., H. H. Lin, H.-T. Deng, K.-J. Kim, H.-M. Shih, D. K. Ann. 2001. Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of α-subunit of epithelial Na+ channel (α-ENaC) transcription by Ras activation in salivary epithelial cells. J. Biol. Chem. 276:29805. (10.1074/jbc.M103153200)
  18. Kotaja, N., M. Vihinen, J. J. Palvimo, O. A. Jänne. 2002. Androgen receptor-interacting protein 3 and other PIAS proteins cooperate with glucocorticoid receptor-interacting protein 1 in steroid receptor-dependent signaling. J. Biol. Chem. 277:17781. (10.1074/jbc.M106354200)
  19. Nakagawa, K., H. Yokosawa. 2002. PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1. FEBS Lett. 530:204. (10.1016/S0014-5793(02)03486-5)
  20. Ross, S., J. L. Best, L. I. Zon, G. Gill. 2002. SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol. Cell. 10:831. (10.1016/S1097-2765(02)00682-2)
  21. Sapetschnig, A., G. Rischitor, H. Braun, A. Doll, M. Schergaut, F. Melchior, and G. Suske, G. 2002. Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO J. 21:5206. (10.1093/emboj/cdf510)
  22. Schmidt, D., S. Müller. 2002. Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc. Natl. Acad. Sci. USA 99:2872. (10.1073/pnas.052559499)
  23. Lee, P. S. W., C. Chang, D. Liu, R. Derynck. 2003. Sumoylation of Smad4, the common Smad mediator of transforming growth factor-β family signaling. J. Biol. Chem. 278:27853. (10.1074/jbc.M301755200)
  24. Long, J., I. Matsuura, D. He, G. Wang, K. Shuai, F. Liu. 2003. Repression of Smad transcriptional activity by PIASy, and inhibitor of activated STAT. Proc. Natl. Acad. Sci. USA 100:9791. (10.1073/pnas.1733973100)
  25. Tussié-Luna, M. I., D. Bayarsaihan, E. Seto, F. H. Ruddle, A. L. Roy. 2002. Physical and functional interactions of histone deacetylase 3 with TFII-I family proteins and PIASxβ. Proc. Natl. Acad. Sci. USA 99:12807. (10.1073/pnas.192464499)
  26. Gross, M., B. Liu, J. Tan, F. S. French, M. Carey, K. Shuai. 2001. Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells. Oncogene 20:3880. (10.1038/sj.onc.1204489)
  27. Liu, B., M. Gross, J. ten Hoeve, K. Shuai. 2001. A transcriptional corepressor of Stat1 with an essential LXXLL signature motif. Proc. Natl. Acad. Sci. USA 98:3203. (10.1073/pnas.051489598)
  28. Wu, L., H. Wu, L. Ma, F. Sangiorgi, N. Wu, J. R. Bell, G. E. Lyons, R. Maxson. 1997. Mix1, a novel zinc finger transcription factor that interacts with Msx2 and enhances its affinity for DNA. Mech. Dev. 65:3. (10.1016/S0925-4773(97)00032-4)
  29. Moilanen, A.-M., U. Karvonen, H. Poukka, W. Yan, J. Toppari, O. A. Janne, J. J. Palvimo. 1999. A testis-specific androgen receptor coregulator that belongs to a novel family of nuclear proteins. J. Biol. Chem. 274:3700. (10.1074/jbc.274.6.3700)
  30. Gill, G.. 2003. Post-translational modification by the small ubiquitin-related modifier SUMO has big effects on transcription factor activity. Curr. Opin. Genet. Dev. 13:108. (10.1016/S0959-437X(03)00021-2)
  31. Kipp, M., F. Gohring, T. Ostendorp, C. M. van Drunen, R. van Driel, M. Pryzybylski, F. O. Fackelmeyer. 2000. SAF-Box, a conserved protein domain that specifically recognizes scaffold attachment region DNA. Mol. Cell. Biol. 20:7480. (10.1128/MCB.20.20.7480-7489.2000)
  32. Hochstrasser, M.. 2000. Evolution and function of ubiquitin-like protein-conjugation systems. Nat. Cell Biol. 2:E153. (10.1038/35019643)
  33. Joazeiro, C. A., A. M. Weissman. 2000. RING finger proteins: mediators of ubiquitin ligase activity. Cell 102:549. (10.1016/S0092-8674(00)00077-5)
  34. Kotaja, N., U. Karvonen, O. A. Jänne, J. J. Palvimo. 2002. PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Mol. Cell. Biol. 22:5222. (10.1128/MCB.22.14.5222-5234.2002)
  35. Nishida, T., H. Yasuda. 2002. PIAS1 and PIASxα function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription.. J. Biol. Chem. 277:41311. (10.1074/jbc.M206741200)
  36. Rogers, R. S., C. M. Horvath, M. J. Matunis. 2003. SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. J. Biol. Chem. 278:30091. (10.1074/jbc.M301344200)
  37. Melchior, F.. 2000. SUMO, nonclassical ubiquitin. Annu. Rev. Cell Dev. Biol. 16:591. (10.1146/annurev.cellbio.16.1.591)
  38. Jackson, P. K.. 2001. A new RING for SUMO: wrestling transcriptional responses into nuclear bodies with PIAS family E3 SUMO ligases. Genes Dev. 15:3053. (10.1101/gad.955501)
  39. Müller, S., C. Hoege, G. Pyrowolakis, S. Jentsch. 2001. SUMO, ubiquitin’s mysterious cousin. Nat. Rev. Mol. Cell Biol. 2:202. (10.1038/35056591)
  40. Ungureanu, D., S. Vanhatupa, N. Kotaja, J. Yang, S. Aittomäki, O. A. Jänne, J. J. Palvimo, O. Silvennoinen. 2003. PIAS proteins promote SUMO-1 conjugation to STAT1. Blood 102:3311. (10.1182/blood-2002-12-3816)
  41. Seeler, J. S., A. Dejean. 2001. SUMO of branched proteins and nuclear bodies. Oncogene 20:7243. (10.1038/sj.onc.1204758)
  42. Poukka, H., U. Karvonen, O. A. Jänne, J. J. Palvimo. 2000. Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). Proc. Natl. Acad. Sci. USA 97:14145. (10.1073/pnas.97.26.14145)
  43. Le Drean, Y., N. Mincheneau, P. Le Goff, D. Michel. 2002. Potentiation of glucocorticoid receptor transcriptional activity by sumoylation. Endocrinology 143:3482. (10.1210/en.2002-220135)
  44. Holmstrom, S., M. E. Van Antwerp, J. A. Iniguez-Lluhi. 2003. Direct and distinguishable inhibitory roles for SUMO isoforms in the control of transcriptional synergy. Proc. Natl. Acad. Sci. USA 100:15758. (10.1073/pnas.2136933100)
  45. Betz, A., N. Lampen, S. Martinek, M. W. Young, J. E. Darnell, Jr. 2001. A Drosophila PIAS homologue negatively regulates stat92E. Proc. Natl. Acad. Sci. USA 98:9563. (10.1073/pnas.171302098)
  46. Hari, K. L., K. R. Cook, G. H. Karpen. 2001. The Drosophila Su(var)2-10 locus regulates chromosome structure and function and encodes a member of the PIAS protein family. Genes Dev. 15:1334. (10.1101/gad.877901)
  47. Strunnikov, A. V., l. Aravind, E. V. Koonin. 2001. Saccharomyces cerevisiae SMT4 encodes an evolutionarily conserved protease with a role in chromosome condensation regulation. Genetics 158:95. (10.1093/genetics/158.1.95)
  48. Sturm, S., M. Koch, F. W. White. 2001. Genomic organization of the gene for mouse PIASy and analysis of its promoter. Gene 266:123. (10.1016/S0378-1119(01)00363-8)
  49. Roth, W., J. Deussing, V. A. Botchkarev, M. Pauly-Evers, P. Saftig, A. Hafner, P. Schmidt, W. Schmahl, J. Scherer, I. Anton-Lamprecht, et al 2000. Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J. 14:2075. (10.1096/fj.99-0970com)
  50. Giese, K., R. Grosschedl. 1993. LEF-1 contains an activation domain that stimulates transcription only in a specific context of factor-binding sites. EMBO J. 12:4667. (10.1002/j.1460-2075.1993.tb06155.x)
  51. Bruhn, L., A. Munnerlyn, R. Grosschedl. 1997. ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCRα enhancer function. Genes Dev. 11:640. (10.1101/gad.11.5.640)
  52. Hsu, S. C., J. Galceran, R. Grosschedl. 1998. Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with β-catenin. Mol. Cell. Biol. 18:4807. (10.1128/MCB.18.8.4807)
  53. Hogan, R., R. Beddington, F. Constantini, E. Lacy. 1994. Manipulating the Mouse Embryo: A Laboratory Manual 2nd Ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
  54. Jenuwein, T., W. C. Forrester, R. G. Qiu, R. Grosschedl. 1993. The immunoglobulin μ enhancer core establishes local factor access in nuclear chromatin independent of transcriptional stimulation. Genes Dev. 7:2016. (10.1101/gad.7.10.2016)
  55. Sturm, S., M. Koch, F. A. White. 2000. Cloning and analysis of a murine PIAS family member, PIASγ, in developing skin and neurons. J. Mol. Neurosci. 14:107. (10.1385/JMN:14:1-2:107)
  56. Durbin, J. E., R. Hackenmiller, M. C. Simon, D. E. Levy. 1996. Targeted disruption of the mouse STAT1 gene results in compromised innate immunity to viral disease. Cell 84:443. (10.1016/S0092-8674(00)81289-1)
  57. Meraz, M. A., J. M. White, K. C. F. Sheehan, E. A. Bach, S. J. Rodig, A. S. Dighe, D. H. Kaplan, J. K. Riley, A. C. Greenlund, D. Campbell, et al 1996. Targeted disruption of the STAT1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84:431. (10.1016/S0092-8674(00)81288-X)
  58. Der, S. D., A. Zhou, B. R. G. Williams, R. H. Silverman. 1998. Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays. Proc. Natl. Acad. Sci. USA 95:15623. (10.1073/pnas.95.26.15623)
  59. Stark, G. R., I. M. Kerr, B. R. Williams, R. H. Silverman, R. D. Schreiber. 1998. Annu. Rev. Biochem. 67:227. (10.1146/annurev.biochem.67.1.227)
  60. Lustig, B., B. Jerchow, M. Sachs, S. Weiler, T. Pietsch, U. Karsten, M. van de Wetering, H. Clevers, P. M. Schlag, W. Birchmeier, J. Behrens. 2002. Negative feedback loop of Wnt signaling through upregulation of conductin/Axin2 in colorectal and liver tumors. Mol. Cell. Biol. 22:1184. (10.1128/MCB.22.4.1184-1193.2002)
  61. Hedgepeth, C. M., L. J. Conrad, J. Zhang, H. C. Huang, V. M. Lee, P. S. Klein. 1997. Activation of the Wnt signalling pathway: a molecular mechanism for lithium action. Dev. Biol. 185:82. (10.1006/dbio.1997.8552)
  62. Dobreva, G., J. Dambacher, R. Grosschedl. 2003. SUMO modification of a novel MAR-binding protein, SATB2, modulates immunoglobulin μ gene expression. Genes Dev. 17:3048. (10.1101/gad.1153003)
  63. Bilovocky, N. A., R. R. Romito-DiGiacomo, C. L. Murcia, S. M. Maricich, K. Herrup. 2003. Factors in the genetic background suppress the Engrailed-1 cerebellar phenotype. J. Neurosci. 23:5105. (10.1523/JNEUROSCI.23-12-05105.2003)
  64. Bromberg, J. F., M. H. Wrzeszczynska, G. Devgan, Y. Zhao, R. Pestell, C. Albanese, J. E. Darnell, Jr. 1999. Stat3 as an oncogene. Cell 98:295. (10.1016/S0092-8674(00)81959-5)
  65. Zhang, Q., P. N. Raghunath, L. Xue, M. Majewski, D. F. Carpentieri, N. Odum, S. Morris, T. Skorski, M. A. Wasik. 2002. Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma. J. Immunol. 168:466. (10.4049/jimmunol.168.1.466)
  66. Thanos, D., T. Maniatis. 1992. The high mobility group protein HMG I(Y) is required for NF-κB dependent virus induction of the human IFN-β gene. Cell 71:777. (10.1016/0092-8674(92)90554-P)
  67. Falvo, J. V., D. Thanos, T. Maniatis. 1995. Reversal of intrinsic DNA bends in the IFN-β gene enhancer by transcription factors and the architectural protein HMG I(Y). Cell 83:1101. (10.1016/0092-8674(95)90137-X)
  68. Falvo, J. V., B. S. Parekh, C. H. Lin, E. Fraenkel, T. Maniatis. 2000. Assembly of a functional β interferon enhanceosome is dependent on ATF-2-c-jun heterodimer orientation. Mol. Cell. Biol. 20:4814. (10.1128/MCB.20.13.4814-4825.2000)
  69. Shuai, K., C. Schindler, V. R. Prezioso, J. E. Darnell, Jr. 1992. Interferon γ triggers transcription through cytoplasmic tyrosine phosphorylation of a 91 kDa DNA-binding protein. Science 258:1808. (10.1126/science.1281555)
  70. Schindler, U., P. Wu, M. Rothe, M. Brasseur, S. L. McKnight. 1995. Components of a Stat recognition code: evidence for two layers of molecular selectivity. Immunity 2:689. (10.1016/1074-7613(95)90013-6)
  71. Larner, A. C., M. David, G. M. Feldman, K. Igarashi, R. H. Hackett, D. S. A. Webb, S. M. Sweitzer, III, E. F. Petricoin, D. S. Finbloom. 1993. Tyrosine phosphorylation of DNA binding proteins by multiple cytokines. Science 261:1730. (10.1126/science.8378773)
  72. Sadowski, H. B., K. Shuai, J. E. Darnell, M. Z. Gilman. 1993. A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science 261:1739. (10.1126/science.8397445)
  73. Raz, R., J. E. Durbin, D. E. Levy. 1994. Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. J. Biol. Chem. 269:24391. (10.1016/S0021-9258(19)51096-1)
  74. Finbloom, D. S., K. D. Winestock. 1995. IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1α and STAT3 complexes in human T cells and monocytes. J. Immunol. 155:1079. (10.4049/jimmunol.155.3.1079)
  75. Dupuis, S., C. Dargemont, C. Fieschi, N. Thomassin, S. Rosenzweig, J. Harris, S. M. Holland, R. D. Schreiber, J.-L. Casanova. 2001. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293:300. (10.1126/science.1061154)
  76. Wong, K. A., R. Kim, H. Christofk, J. Gao, G. Lawson, H. Wu. 2004. Protein inhibitor of activated STAT Y (PIASy) and a splice variant lacking exon 6 enhance sumoylation but are not essential for embryogenesis and adult life. Mol. Cell. Biol. 24:5577. (10.1128/MCB.24.12.5577-5586.2004)
Dates
Type When
Created 11 years, 4 months ago (April 20, 2014, 8:57 p.m.)
Deposited 8 months ago (Jan. 2, 2025, 1:44 p.m.)
Indexed 4 months, 3 weeks ago (April 10, 2025, 7:12 a.m.)
Issued 20 years, 9 months ago (Nov. 15, 2004)
Published 20 years, 9 months ago (Nov. 15, 2004)
Published Print 20 years, 9 months ago (Nov. 15, 2004)
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@article{Roth_2004, title={PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling}, volume={173}, ISSN={1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.173.10.6189}, DOI={10.4049/jimmunol.173.10.6189}, number={10}, journal={The Journal of Immunology}, publisher={Oxford University Press (OUP)}, author={Roth, Wera and Sustmann, Claudio and Kieslinger, Matthias and Gilmozzi, Andrea and Irmer, Denis and Kremmer, Elisabeth and Turck, Chris and Grosschedl, Rudolf}, year={2004}, month=nov, pages={6189–6199} }