Pim1 promotes IFN-β production by interacting with IRF3
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The Pim (proviral integration site for Moloney murine leukemia virus) proteins compose a serine threonine kinase family whose members regulate cell proliferation, migration and cell survival. However, whether Pim kinases participate in innate immune responses is unclear. Here, we show for the first time that Pim1 plays an essential role in the production of interferon (IFN)-β by macrophages after their Toll-like receptor (TLR) pathway is activated by pathogen-associated molecular patterns (PAMPs). Specifically, Pim1 was quickly upregulated in an NF-κB-dependent manner after TLR stimulation with PAMPs. Pim1 deficiency reduced TLR3- or TLR4-stimulated IFN-β and IFN-stimulated gene (ISG) expression but not proinflammatory cytokine expression in macrophages. Mechanistically, Pim1 specifically upregulates IRF3 phosphorylation and nuclear translocation. However, this role is not dependent on Pim1 kinase activity. Rather, Pim1 appears to promote IRF3 phosphorylation by enhancing the formation of IFN-β signaling complexes composed of TRIF, TRAF3, TBK1, and IRF3. Poly (I:C)-treated Pim1−/− mice produced less serum IFN-β and were less likely to survive than wild-type mice. These findings show for the first time that Pim1 participates in TLR-mediated IFN-β production, thus revealing a novel target for controlling antiviral innate immune responses.
Abstract
The Pim (proviral integration site for Moloney murine leukemia virus) proteins compose a serine threonine kinase family whose members regulate cell proliferation, migration and cell survival. However, whether Pim kinases participate in innate immune responses is unclear. Here, we show for the first time that Pim1 plays an essential role in the production of interferon (IFN)-β by macrophages after their Toll-like receptor (TLR) pathway is activated by pathogen-associated molecular patterns (PAMPs). Specifically, Pim1 was quickly upregulated in an NF-κB-dependent manner after TLR stimulation with PAMPs. Pim1 deficiency reduced TLR3- or TLR4-stimulated IFN-β and IFN-stimulated gene (ISG) expression but not proinflammatory cytokine expression in macrophages. Mechanistically, Pim1 specifically upregulates IRF3 phosphorylation and nuclear translocation. However, this role is not dependent on Pim1 kinase activity. Rather, Pim1 appears to promote IRF3 phosphorylation by enhancing the formation of IFN-β signaling complexes composed of TRIF, TRAF3, TBK1, and IRF3. Poly (I:C)-treated Pim1−/− mice produced less serum IFN-β and were less likely to survive than wild-type mice. These findings show for the first time that Pim1 participates in TLR-mediated IFN-β production, thus revealing a novel target for controlling antiviral innate immune responses.
참고문헌 (61)
- Akira, S., "Toll-like receptor signalling", Nat. Rev. Immunol, 4, pp.499~511 (2004)
- Kawai, T., "The role of pattern-recognition receptors in innate immunity : update on Toll-like receptors", Nat. Immunol, 11, pp.373~384 (2010)
- Brubaker, S. W., "Innate immune pattern recognition : a cell biological perspective", Annu. Rev. Immunol, 33, pp.257~290 (2015)
- Takeuchi, O., "Innate immunity to virus infection", Immunol. Rev, 227, pp.75~86 (2009)
- Kagan, J. C., "SMOCs: supramolecular organizing centres that control innate immunity", Nat. Rev. Immunol, 14, pp.821~826 (2014)
- Matsumoto, M., "TLR3 : interferon induction by double-stranded RNA including poly(I : C)", Adv. Drug. Deliv. Rev, 60, pp.805~812 (2008)
- Kagan, J. C., "TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta", Nat. Immunol, 9, pp.361~368 (2008)
- Yamamoto, M., "Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway", Science, 301, pp.640~643 (2003)
- Liu, S., "Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation", Science, 347, pp.aaa2630~ (2015)
- Fitzgerald, K. A., "Toll-like receptors and the control of immunity", Cell, 180, pp.1044~1066 (2020)
- Fitzgerald, K. A., "IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway", Nat. Immunol, 4, pp.491~496 (2003)
- McWhirter, S. M., "IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts", Proc. Natl Acad. Sci. USA, 101, pp.233~238 (2004)
- Hiscott, J., "Triggering the innate antiviral response through IRF-3 activation", J. Biol. Chem, 282, pp.15325~15329 (2007)
- Yanai, H., "Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice", Proc. Natl Acad. Sci. USA, 115, pp.5253~5258 (2018)
- Schneider, W. M., "Interferon-stimulated genes : a complex web of host defenses", Annu. Rev. Immunol, 32, pp.513~545 (2014)
- Sheikh, F., "An essential role for IFN-beta in the induction of IFN-stimulated gene expression by LPS in macrophages", J. Leukoc. Biol, 96, pp.591~600 (2014)
- Jinesh, G. G., "Pim kinase isoforms : devils defending cancer cells from therapeutic and immune attacks", Apoptosis, 21, pp.1203~1213 (2016)
- Saris, C. J., "The pim-1 oncogene encodes two related protein-serine", threonine kinases by alternative initiation at AUG and CUG, 1991, pp.10, 655~664
- Meeker, T. C., "Characterization of the human PIM-1 gene : a putative protooncogene coding for a tissue specific member of the protein kinase family", Oncogene Res, 1, pp.87~101 (1987)
- Baytel, D., "The human Pim-2proto-oncogene and its testicular expression", Biochim. Biophys. Acta, 1442, pp.274~285 (1998)
- Fujii, C., "Aberrant expression of serine", threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines, 2005, pp.114, 209~218
- Bachmann, M., "The serine", threonine kinase Pim-1, 2005, pp.37, 726~730
- Tursynbay, Y., "Pim-1 kinase as cancer drug target : an update", Biomed. Rep, 4, pp.140~146 (2016)
- Morishita, D., "Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels", Cancer Res, 68, pp.5076~5085 (2008)
- Beharry, Z., "The Pim protein kinases regulate energy metabolism and cell growth", Proc. Natl Acad. Sci. USA, 108, pp.528~533 (2011)
- Zhang, Y., "Pim kinase-dependent inhibition of c-Myc degradation", Oncogene, 27, pp.4809~4819 (2008)
- Dang, Y., "Proto-oncogene serine", threonine kinase PIM3 promotes cell migration via modulating Rho GTPase signaling, 2020, pp.19, 1298~1309
- Lilly, M., "The PIM-1 serine kinase prolongs survival and inhibits apoptosis-related mitochondrial dysfunction in part through a bcl-2-dependent pathway", Oncogene, 18, pp.4022~4031 (1999)
- Yan, B., "The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death", J. Biol. Chem, 278, pp.45358~45367 (2003)
- Muraski, J. A., "Pim-1 regulates cardiomyocyte survival downstream of Akt", Nat. Med, 13, pp.1467~1475 (2007)
- Hu, X. F., "PIM-1-specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis", J. Clin. Invest, 119, pp.362~375 (2009)
- Nawijn, M. C., "For better or for worse: the role of Pim oncogenes in tumorigenesis", Nat. Rev. Cancer, 11, pp.23~34 (2011)
- Braso-Maristany, F., "PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer", Nat. Med, 22, pp.1303~1313 (2016)
- Liu, Z., "The role of Pim kinase in immunomodulation", Am. J. Cancer Res, 10, pp.4085~4097 (2020)
- Moroy, T., "Expression of a Pim-1transgene accelerates lymphoproliferation and inhibits apoptosis in lpr", lpr mice, 1993, pp.90, 10734~10738
- Rainio, E. M., "Cutting edge : transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase", J. Immunol, 168, pp.1524~1527 (2002)
- Peperzak, V., "The Pim kinase pathway contributes to survival signaling in primed CD8+ T cells upon CD27 costimulation", J. Immunol, 185, pp.6670~6678 (2010)
- Knudson, K. M., "NFkappaB-Pim-1-Eomesodermin axis is critical for maintaining CD8 T-cell memory quality", Proc. Natl Acad. Sci. USA, 114, pp.E1659~E1667 (2017)
- Banerjee, S., "EBNA3C augments Pim-1 mediated phosphorylation and degradation of p21 to promote B-cell proliferation", PLoS Pathog, 10, pp.e1004304~ (2014)
- Daenthanasanmak, A., "PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity", J. Clin. Invest, 128, pp.2787~2801 (2018)
- Guo, Q., "Immunotherapy for hepatoma using a dual-function vector with both immunostimulatory and pim-3-silencing effects", Mol. Cancer Ther, 13, pp.1503~1513 (2014)
- Tahvanainen, J., "Proviral integration site for Moloney murine leukemia virus(PIM)kinases promote human T helper 1 cell differentiation", J. Biol. Chem, 288, pp.3048~3058 (2013)
- Zhang, X., "Identification of new type I interferon-stimulated genes and investigation of their involvement in IFN-beta activation", Protein Cell, 9, pp.799~807 (2018)
- Zhou, F., "PIM1 kinase facilitates Zika virus replication by suppressing host cells’ natural immunity", Signal Transduct. Target. Ther, 6, pp.207~ (2021)
- Kim, K., "Pim-1 regulates RANKL-induced osteoclastogenesis via NF-kappaB activation and NFATc1 induction", J. Immunol, 185, pp.7460~7466 (2010)
- Ko, R., "Glycogen synthase kinase 3beta regulates antiviral responses of TLR3via TRAF2-Src axis", J. Immunol, 203, pp.2990~2999 (2019)
- Ko, R., "Glycogen synthase kinase 3beta ubiquitination by TRAF6 regulates TLR3-mediated pro-inflammatory cytokine production", Nat. Commun, 6, pp.6765~ (2015)
- Barbalat, R., "Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands", Nat. Immunol, 10, pp.1200~1207 (2009)
- Oosenbrug, T., "An alternative model for type I interferon induction downstream of human TLR2", J. Biol. Chem, 295, pp.14325~14342 (2020)
- Rehwinkel, J., "RIG-I-like receptors : their regulation and roles in RNA sensing", Nat. Rev. Immunol, 20, pp.537~551 (2020)
- Sun, L., "Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway", Science, 339, pp.786~791 (2013)
- Joung, S. M., "Akt contributes to activation of the TRIF-dependent signaling pathways of TLRs by interacting with TANK-binding kinase 1", J. Immunol, 186, pp.499~507 (2011)
- Hacker, H., "Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6", Nature, 439, pp.204~207 (2006)
- Oganesyan, G., "Critical role of TRAF3 in the Toll-like receptor-dependent and-independent antiviral response", Nature, 439, pp.208~211 (2006)
- Yang, K., "Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells", Mol. Biol. Cell, 17, pp.1461~1471 (2006)
- de Vries, M., "Inhibition of Pim1 kinase reduces viral replication in primary bronchial epithelial cells", Eur. Respir. J, 45, pp.1745~1748 (2015)
- Park, C., "Pim kinase interacts with nonstructural 5A protein and regulates hepatitis C virus entry", J. Virol, 89, pp.10073~10086 (2015)
- Zhou, F., "Pim1 impacts enterovirus A71 replication and represents a potential target in antiviral therapy", iScience, 19, pp.715~727 (2019)
- Volberding, P. J., "Suppressive neutrophils require PIM1 for metabolic fitness and survival during chronic viral infection", Cell rep, 35, pp.109160~ (2021)
- Sugasti-Salazar, M., "Targeting host PIM protein kinases reduces mayaro virus replication", Viruses, 14, pp.422~ (2022)
- Lei, C. Q., "Glycogen synthase kinase 3beta regulates IRF3 transcription factormediated antiviral response via activation of the kinase TBK1", Immunity, 33, pp.878~889 (2010)