Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

STING Negatively Regulates Double-Stranded DNA-Activated JAK1-STAT1 Signaling via SHP-1/2 in B Cells

  • Dong, Guanjun (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University) ;
  • You, Ming (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University) ;
  • Ding, Liang (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University) ;
  • Fan, Hongye (State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University) ;
  • Liu, Fei (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University) ;
  • Ren, Deshan (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University) ;
  • Hou, Yayi (The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University)
  • Received : 2014.12.31
  • Accepted : 2015.02.26
  • Published : 2015.05.31
Download PDF
⟨ Previous Next ⟩

Abstract

Recognition of cytosolic DNA initiates a series of innate immune responses by inducing IFN-I production and subsequent triggering JAK1-STAT1 signaling which plays critical roles in the pathogenesis of infection, inflammation and autoimmune diseases through promoting B cell activation and antibody responses. The stimulator of interferon genes protein (STING) has been demonstrated to be a critical hub of type I IFN induction in cytosolic DNA-sensing pathways. However, it still remains unknown whether cytosolic DNA can directly activate the JAK1-STAT1 signaling or not. And the role of STING is also unclear in this response. In the present study, we found that dsDNA directly triggered the JAK1-STAT1 signaling by inducing phosphorylation of the Lyn kinase. Moreover, this response is not dependent on type I IFN receptors. Interestingly, STING could inhibit dsDNA-triggered activation of JAK1-STAT1 signaling by inducing SHP-1 and SHP-2 phosphorylation. In addition, compared with normal B cells, the expression of STING was significantly lower and the phosphorylation level of JAK1 was significantly higher in B cells from MRL/lpr lupus-prone mice, highlighting the close association between STING low-expression and JAK1-STAT1 signaling activation in B cells in autoimmune diseases. Our data provide a molecular insight into the novel role of STING in dsDNA-mediated inflammatory disorders.

Keywords

References

  1. Ahn, J., Gutman, D., Saijo, S., and Barber, G.N. (2012). STING manifests self DNA-dependent inflammatory disease. Proc. Natl. Acad. Sci. USA 109, 19386-19391. https://doi.org/10.1073/pnas.1215006109
  2. Ahn, J., Ruiz, P., and Barber, G.N. (2014a). Intrinsic self-DNA triggers inflammatory disease dependent on STING. J. Immunol. 193, 4634-4642. https://doi.org/10.4049/jimmunol.1401337
  3. Ahn, J., Xia, T., Konno, H., Konno, K., Ruiz, P., and Barber, G.N. (2014b). Inflammation-driven carcinogenesis is mediated through STING. Nat. Commun. 5, 5166. https://doi.org/10.1038/ncomms6166
  4. Al-Shami, A., and Naccache, P.H. (1999). Granulocyte-macrophage colony-stimulating factor-activated signaling pathways in human neutrophils. Involvement of Jak2 in the stimulation of phosphatidylinositol 3-kinase. J. Biol. Chem. 274, 5333-5338. https://doi.org/10.1074/jbc.274.9.5333
  5. Alexander, W.S., and Hilton, D.J. (2004). The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu. Rev. Immunol. 22, 503-529. https://doi.org/10.1146/annurev.immunol.22.091003.090312
  6. Baechler, E.C., Batliwalla, F.M., Karypis, G., Gaffney, P.M., Ortmann, W.A., Espe, K.J., Shark, K.B., Grande, W.J., Hughes, K.M., Kapur, V., et al. (2003). Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl. Acad. Sci. USA 100, 2610-2615. https://doi.org/10.1073/pnas.0337679100
  7. Barbalat, R., Ewald, S.E., Mouchess, M.L., and Barton, G.M. (2011). Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185-214. https://doi.org/10.1146/annurev-immunol-031210-101340
  8. Barber, G.N. (2011). Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses. Curr. Opin. Immunol. 23, 10-20. https://doi.org/10.1016/j.coi.2010.12.015
  9. Baum, R., Sharma, S., Carpenter, S., Li, Q. Z., Busto, P., Fitzgerald, K.A., Marshak-Rothstein, A., and Gravallese, E.M. (2015). Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase iI-deficient mice. J. Immunol. 194, 873-877. https://doi.org/10.4049/jimmunol.1402573
  10. Becker, A. M., Dao, K.H., Han, B.K., Kornu, R., Lakhanpal, S., Mobley, A.B., Li, Q.Z., Lian, Y., Wu, T., Reimold, A.M., et al. (2013). SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PLoS One 8, e67003. https://doi.org/10.1371/journal.pone.0067003
  11. Bennett, L., Palucka, A.K., Arce, E., Cantrell, V., Borvak, J., Banchereau, J., and Pascual, V. (2003). Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711-723. https://doi.org/10.1084/jem.20021553
  12. Biron, C.A., Byron, K.S., and Sullivan, J.L. (1989). Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731-1735. https://doi.org/10.1056/NEJM198906293202605
  13. Bromberg, J. F., Fan, Z., Brown, C., Mendelsohn, J., and Darnell, J. E., Jr. (1998). Epidermal growth factor-induced growth inhibition requires Stat1 activation. Cell Growth Differ. 9, 505-512.
  14. Bunde, T., Kirchner, A., Hoffmeister, B., Habedank, D., Hetzer, R., Cherepnev, G., Proesch, S., Reinke, P., Volk, H.D., Lehmkuhl, H., et al. (2005). Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J. Exp. Med. 201, 1031-1036. https://doi.org/10.1084/jem.20042384
  15. Burdette, D.L., and Vance, R.E. (2013). STING and the innate immune response to nucleic acids in the cytosol. Nat. Immunol. 14, 19-26.
  16. Carlton-Smith, C., and Elliott, R.M. (2012). Viperin, MTAP44, and protein kinase R contribute to the interferon-induced inhibition of Bunyamwera Orthobunyavirus replication. J. Virol. 86, 11548-11557. https://doi.org/10.1128/JVI.01773-12
  17. Chen, H., Sun, H., You, F., Sun, W., Zhou, X., Chen, L., Yang, J., Wang, Y., Tang, H., Guan, Y., et al. (2011). Activation of STAT6 by STING is critical for antiviral innate immunity. Cell 147, 436-446. https://doi.org/10.1016/j.cell.2011.09.022
  18. Chiu, Y.H., Macmillan, J.B., and Chen, Z.J. (2009). RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576-591. https://doi.org/10.1016/j.cell.2009.06.015
  19. Christensen, S.R., Shupe, J., Nickerson, K., Kashgarian, M., Flavell, R.A., and Shlomchik, M.J. (2006). Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417-428. https://doi.org/10.1016/j.immuni.2006.07.013
  20. Cohen, P.L., Caricchio, R., Abraham, V., Camenisch, T.D., Jennette, J.C., Roubey, R.A., Earp, H.S., Matsushima, G., and Reap, E.A. (2002). Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exp. Med. 196, 135-140. https://doi.org/10.1084/jem.20012094
  21. Crow, M.K. (2007). Type I interferon in systemic lupus erythematosus. Curr. Top. Microbiol. Immunol. 316, 359-386.
  22. Darnell, J.E., Jr. (1997). STATs and gene regulation. Science 277, 1630-1635. https://doi.org/10.1126/science.277.5332.1630
  23. Darnell, J.E., Jr., Kerr, I.M., and Stark, G.R. (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415-1421. https://doi.org/10.1126/science.8197455
  24. Dedeoglu, F. (2009). Drug-induced autoimmunity. Curr. Opin. Rheumatol. 21, 547-551. https://doi.org/10.1097/BOR.0b013e32832f13db
  25. Diamond, M.S., and Farzan, M. (2013). The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat. Rev. Immunol. 13, 46-57. https://doi.org/10.1038/nri3344
  26. Fensterl, V., and Sen, G.C. (2011). The ISG56/IFIT1 gene family. J. Interferon Cytokine Res. 31, 71-78. https://doi.org/10.1089/jir.2010.0101
  27. Frese, S., and Diamond, B. (2011). Structural modification of DNA-- a therapeutic option in SLE? Nat. Rev. Rheumatol. 7, 733-738. https://doi.org/10.1038/nrrheum.2011.153
  28. Gourley, M. and Miller, F.W. (2007). Mechanisms of disease: Environmental factors in the pathogenesis of rheumatic disease. Nat. Clin. Pract. Rheumatol. 3, 172-180. https://doi.org/10.1038/ncprheum0435
  29. Hallen, L.C., Burki, Y., Ebeling, M., Broger, C., Siegrist, F., Oroszlan- Szovik, K., Bohrmann, B., Certa, U., and Foser, S. (2007). Antiproliferative activity of the human IFN-alpha-inducible protein IFI44. J. Interferon Cytokine Res. 27, 675-680. https://doi.org/10.1089/jir.2007.0021
  30. Haller, O., Kochs, G., and Weber, F. (2007). Interferon, Mx, and viral countermeasures. Cytokine Growth Factor Rev. 18, 425-433. https://doi.org/10.1016/j.cytogfr.2007.06.001
  31. Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D.R., Latz, E., and Fitzgerald, K.A. (2009). AIM2 recognizes cytosolic dsDNA and forms a caspase-1- activating inflammasome with ASC. Nature 458, 514-518. https://doi.org/10.1038/nature07725
  32. Ishii, K.J., Coban, C., Kato, H., Takahashi, K., Torii, Y., Takeshita, F., Ludwig, H., Sutter, G., Suzuki, K., Hemmi, H., et al. (2006). A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7, 40-48. https://doi.org/10.1038/ni1282
  33. Ishikawa, H., and Barber, G.N. (2008). STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674-678. https://doi.org/10.1038/nature07317
  34. Ishikawa, H., Ma, Z., and Barber, G.N. (2009). STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788-792. https://doi.org/10.1038/nature08476
  35. Javierre, B.M., Hernando, H., and Ballestar, E. (2011). Environmental triggers and epigenetic deregulation in autoimmune disease. Discov. Med. 12, 535-545.
  36. Justesen, J., Hartmann, R., and Kjeldgaard, N.O. (2000). Gene structure and function of the 2'-5'-oligoadenylate synthetase family. Cell. Mol. Life Sci. 57, 1593-1612. https://doi.org/10.1007/PL00000644
  37. Klingmuller, U., Lorenz, U., Cantley, L.C., Neel, B.G., and Lodish, H.F. (1995). Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80, 729-738. https://doi.org/10.1016/0092-8674(95)90351-8
  38. Lau, C.M., Broughton, C., Tabor, A.S., Akira, S., Flavell, R.A., Mamula, M.J., Christensen, S. R., Shlomchik, M.J., Viglianti, G.A., Rifkin, I. R., et al. (2005). RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171-1177. https://doi.org/10.1084/jem.20050630
  39. Le Bon, A., Schiavoni, G., D'Agostino, G., Gresser, I., Belardelli, F., and Tough, D.F. (2001). Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14, 461-470. https://doi.org/10.1016/S1074-7613(01)00126-1
  40. Lemos, H., Huang, L., Chandler, P.R., Mohamed, E., Souza, G.R., Li, L., Pacholczyk, G., Barber, G.N., Hayakawa, Y., Munn, D.H., et al. (2014). Activation of the STING adaptor attenuates experimental autoimmune encephalitis. J. Immunol. 192, 5571-5578. https://doi.org/10.4049/jimmunol.1303258
  41. Mathian, A., Gallegos, M., Pascual, V., Banchereau, J., and Koutouzov, S. (2011). Interferon-alpha induces unabated production of short-lived plasma cells in pre-autoimmune lupusprone (NZBxNZW)F1 mice but not in BALB/c mice. Eur. J. Immunol. 41, 863-872. https://doi.org/10.1002/eji.201040649
  42. Paludan, S.R., and Bowie, A.G. (2013). Immune sensing of DNA. Immunity 38, 870-880. https://doi.org/10.1016/j.immuni.2013.05.004
  43. Perez-Mercado, A.E., and Vila-Perez, S. (2010). Cytomegalovirus as a trigger for systemic lupus erythematosus. J. Clin. Rheumatol. 16, 335-337. https://doi.org/10.1097/RHU.0b013e3181f4cf52
  44. Platanias, L.C. (2005). Mechanisms of type-I- and type-II-interferonmediated signalling. Nat. Rev. Immunol. 5, 375-386. https://doi.org/10.1038/nri1604
  45. Sarzi-Puttini, P., Atzeni, F., Iaccarino, L., and Doria, A. (2005). Environment and systemic lupus erythematosus: an overview. Autoimmunity 38, 465-472. https://doi.org/10.1080/08916930500285394
  46. Sfriso, P., Ghirardello, A., Botsios, C., Tonon, M., Zen, M., Bassi, N., Bassetto, F., and Doria, A. (2010). Infections and autoimmunity: the multifaceted relationship. J. Leukoc. Biol. 87, 385-395. https://doi.org/10.1189/jlb.0709517
  47. Sharma, S., Campbell, A.M., Chan, J., Schattgen, S.A., Orlowski, G. M., Nayar, R., Huyler, A. H., Nundel, K., Mohan, C., Berg, L.J., et al. (2015). Suppression of systemic autoimmunity by the innate immune adaptor STING. Proc. Natl. Acad. Sci. USA 112, E710-E717. https://doi.org/10.1073/pnas.1420217112
  48. Shoenfeld, N., Amital, H., and Shoenfeld, Y. (2009). The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease. Nat. Clin. Pract. Rheumatol. 5, 99-105. https://doi.org/10.1038/ncprheum0989
  49. Simon, H.U., Yousefi, S., Dibbert, B., Levi-Schaffer, F., and Blaser, K. (1997). Anti-apoptotic signals of granulocyte-macrophage colony-stimulating factor are transduced via Jak2 tyrosine kinase in eosinophils. Eur. J. Immunol. 27, 3536-3539. https://doi.org/10.1002/eji.1830271256
  50. Stetson, D.B., and Medzhitov, R. (2006). Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93-103. https://doi.org/10.1016/j.immuni.2005.12.003
  51. Sun, W., Li, Y., Chen, L., Chen, H., You, F., Zhou, X., Zhou, Y., Zhai, Z., Chen, D., and Jiang, Z. (2009). ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc. Natl. Acad. Sci. USA 106, 8653-8658. https://doi.org/10.1073/pnas.0900850106
  52. Swanson, C.L., Wilson, T.J., Strauch, P., Colonna, M., Pelanda, R., and Torres, R.M. (2010). Type I IFN enhances follicular B cell contribution to the T cell-independent antibody response. J. Exp. Med. 207, 1485-1500. https://doi.org/10.1084/jem.20092695
  53. Takaoka, A., Wang, Z., Choi, M. K., Yanai, H., Negishi, H., Ban, T., Lu, Y., Miyagishi, M., Kodama, T., Honda, K., et al. (2007). DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501-505. https://doi.org/10.1038/nature06013
  54. Tsokos, G.C. (2011). Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110-2121. https://doi.org/10.1056/NEJMra1100359
  55. Uccellini, M. B., Busconi, L., Green, N. M., Busto, P., Christensen, S. R., Shlomchik, M. J., Marshak-Rothstein, A., and Viglianti, G.A. (2008). Autoreactive B cells discriminate CpG-rich and CpGpoor DNA and this response is modulated by IFN-alpha. J. Immunol. 181, 5875-5884. https://doi.org/10.4049/jimmunol.181.9.5875
  56. Vachon, V. K., Calderon, B. M., and Conn, G. L. (2015). A novel RNA molecular signature for activation of 2'-5' oligoadenylate synthetase-1. Nucleic Acids Res. 43, 544-552. https://doi.org/10.1093/nar/gku1289
  57. Velazquez, L., Fellous, M., Stark, G. R., and Pellegrini, S. (1992). A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell 70, 313-322. https://doi.org/10.1016/0092-8674(92)90105-L
  58. Vinuesa, C.G., and Goodnow, C.C. (2002). Immunology: DNA drives autoimmunity. Nature 416, 595-598. https://doi.org/10.1038/416595a
  59. Wang, H., Yang, Y., Sharma, N., Tarasova, N.I., Timofeeva, O.A., Winkler-Pickett, R.T., Tanigawa, S., and Perantoni, A.O. (2010). STAT1 activation regulates proliferation and differentiation of renal progenitors. Cell. Signal. 22, 1717-1726. https://doi.org/10.1016/j.cellsig.2010.06.012
  60. Watson, R.O., Manzanillo, P.S., and Cox, J.S. (2012). Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150, 803-815. https://doi.org/10.1016/j.cell.2012.06.040
  61. Wu, J., Sun, L., Chen, X., Du, F., Shi, H., Chen, C., and Chen, Z.J. (2013). Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826-830. https://doi.org/10.1126/science.1229963
  62. Yan, H., Krishnan, K., Greenlund, A.C., Gupta, S., Lim, J.T., Schreiber, R.D., Schindler, C.W., and Krolewski, J.J. (1996). Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein. EMBO J. 15, 1064-1074.
  63. Yang, P., An, H., Liu, X., Wen, M., Zheng, Y., Rui, Y., and Cao, X. (2010). The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a beta-catenin-dependent pathway. Nat. Immunol. 11, 487-494. https://doi.org/10.1038/ni.1876
  64. Yin, T., Shen, R., Feng, G.S., and Yang, Y.C. (1997). Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases. J. Biol. Chem. 272, 1032-1037. https://doi.org/10.1074/jbc.272.2.1032
  65. Zhong, B., Yang, Y., Li, S., Wang, Y. Y., Li, Y., Diao, F., Lei, C., He, X., Zhang, L., Tien, P., et al. (2008). The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538-550. https://doi.org/10.1016/j.immuni.2008.09.003

Cited by

  1. The function of feline stimulator of interferon gene (STING) is evolutionarily conserved vol.169, 2016, https://doi.org/10.1016/j.vetimm.2015.12.005
  2. To Extinguish the Fire from Outside the Cell or to Shutdown the Gas Valve Inside? Novel Trends in Anti-Inflammatory Therapies vol.16, pp.9, 2015, https://doi.org/10.3390/ijms160921277
  3. Stimulator of interferon genes (STING): A “new chapter” in virus-associated cancer research. Lessons from wild-derived mouse models of innate immunity vol.29, 2016, https://doi.org/10.1016/j.cytogfr.2016.02.009
  4. Implication of protein tyrosine phosphatase SHP-1 in cancer-related signaling pathways vol.12, pp.10, 2016, https://doi.org/10.2217/fon-2015-0057
  5. Delicate regulation of the cGAS–MITA-mediated innate immune response vol.15, pp.7, 2018, https://doi.org/10.1038/cmi.2016.51
  6. Nucleic Acid–Sensing Receptors: Rheostats of Autoimmunity and Autoinflammation vol.195, pp.8, 2015, https://doi.org/10.4049/jimmunol.1500964
  7. Innate Immune Sensing by Cells of the Adaptive Immune System vol.11, pp.None, 2015, https://doi.org/10.3389/fimmu.2020.01081
  8. Deficiency of STING Promotes Collagen-Specific Antibody Production and B Cell Survival in Collagen-Induced Arthritis vol.11, pp.None, 2015, https://doi.org/10.3389/fimmu.2020.01101
  9. STING couples with PI3K to regulate actin reorganization during BCR activation vol.6, pp.17, 2015, https://doi.org/10.1126/sciadv.aax9455
  10. Aligned Expression of IFI16 and STING Genes in RRMS Patients’ Blood vol.20, pp.6, 2015, https://doi.org/10.2174/1871530319666190729112246
  11. Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes vol.10, pp.2, 2015, https://doi.org/10.3390/antiox10020334
  12. A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology vol.66, pp.None, 2015, https://doi.org/10.1016/j.ebiom.2021.103314
  13. SHP2-Mediated Inhibition of DNA Repair Contributes to cGAS–STING Activation and Chemotherapeutic Sensitivity in Colon Cancer vol.81, pp.12, 2015, https://doi.org/10.1158/0008-5472.can-20-3738
  14. Extracts of Waste from Poplar Wood Processing Alleviate Experimental Dextran Sulfate-Induced Colitis by Ameliorating Oxidative Stress, Inhibiting the Th1/Th17 Response and Inducing Apoptosis in Inflam vol.10, pp.11, 2015, https://doi.org/10.3390/antiox10111684