Virologica Sinica

, Volume 31, Issue 6, pp 457–465 | Cite as

Roles of IκB kinase ε in the innate immune defense and beyond

Review

Abstract

IκB kinase ε (IKKε) is a non-canonical IκB kinase that is extensively studied in the context of innate immune response. Recently, significant progress has been made in understanding the role of IKKε in interferon (IFN) signaling. In addition to its roles in innate immunity, recent studies also demonstrate that IKKε is a key regulator of the adaptive immune response. Specifically, IKKε functions as a negative feedback kinase to curtail CD8 T cell response, implying that it can be a potential therapeutic target to boost antiviral and antitumor T cell immunity. In this review, we highlight the roles of IKKε in regulating IFN signaling and T cell immunity, and discuss a few imminent questions that remain to be answered.

Keywords

IκB kinase ε (IKKε) antiviral immune response IFN signaling T cell immunity 

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References

  1. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, Yamasaki N, Miyakawa T, Francke U, Graef IA, Crabtree GR. 2006. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature, 441: 595–600.CrossRefPubMedGoogle Scholar
  2. Basler CF, Mikulasova A, Martinez-Sobrido L, Paragas J, Muhlberger E, Bray M, Klenk HD, Palese P, Garcia-Sastre A. 2003. The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. J Virol, 77: 7945–7956.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bharaj P, Wang YE, Dawes BE, Yun TE, Park A, Yen B, Basler CF, Freiberg AN, Lee B, Rajsbaum R. 2016. The Matrix Protein of Nipah Virus Targets the E3-Ubiquitin Ligase TRIM6 to Inhibit the IKKepsilon Kinase-Mediated Type-I IFN Antiviral Response. PLoS Pathog, 12: e1005880.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, Sjostrom SK, Garraway LA, Weremowicz S, Richardson AL, Greulich H, Stewart CJ, Mulvey LA, Shen RR, Ambrogio L, Hirozane-Kishikawa T, Hill DE, Vidal M, Meyerson M, Grenier JK, Hinkle G, Root DE, Roberts TM, Lander ES, Polyak K, Hahn WC. 2007. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell, 129: 1065–1079.CrossRefPubMedGoogle Scholar
  5. Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, Itie A, Wakeham A, Shahinian A, Henzel WJ, Elia AJ, Shillinglaw W, Mak TW, Cao Z, Yeh WC. 2000. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription. EMBO J, 19: 4976–4985.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Brubaker SW, Bonham KS, Zanoni I, Kagan JC. 2015. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol, 33: 257–290.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Cardenas WB, Loo YM, Gale M, Jr., Hartman AL, Kimberlin CR, Martinez-Sobrido L, Saphire EO, Basler CF. 2006. Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. J Virol, 80: 5168–5178.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Challa S, Guo JP, Ding X, Xu CX, Li Y, Kim D, Smith MA, Cress DW, Coppola D, Haura EB, Cheng JQ. 2016. IKBKE Is a Substrate of EGFR and a Therapeutic Target in Non-Small Cell Lung Cancer with Activating Mutations of EGFR. Cancer Res, 76: 4418–4429.CrossRefPubMedGoogle Scholar
  9. Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, Ma JT, Zhou J, Qi N, Westcott D, Delproposto JB, Blackwell TS, Yull FE, Saltiel AR. 2009. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell, 138: 961–975.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Clark K, Peggie M, Plater L, Sorcek RJ, Young ER, Madwed JB, Hough J, McIver EG, Cohen P. 2010. Novel cross-talk within the IKK family controls innate immunity. Biochem J, 434: 93–104.CrossRefGoogle Scholar
  11. Clark K, Plater L, Peggie M, Cohen P. 2009. Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation. J Biol Chem, 284: 14136–14146.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Clement JF, Meloche S, Servant MJ. 2008. The IKK-related kinases: from innate immunity to oncogenesis. Cell Res, 18: 889–899.CrossRefPubMedGoogle Scholar
  13. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T. 2003. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol, 4: 491–496.CrossRefPubMedGoogle Scholar
  14. Gulen MF, Bulek K, Xiao H, Yu M, Gao J, Sun L, Beurel E, Kaidanovich-Beilin O, Fox PL, DiCorleto PE, Wang JA, Qin J, Wald DN, Woodgett JR, Jope RS, Carman J, Dongre A, Li X. 2012. Inactivation of the enzyme GSK3alpha by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates interleukin-1-induced Th17 cell maintenance. Immunity, 37: 800–812.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Guo JP, Shu SK, He L, Lee YC, Kruk PA, Grenman S, Nicosia SV, Mor G, Schell MJ, Coppola D, Cheng JQ. 2009. Deregulation of IKBKE is associated with tumor progression, poor prognosis, and cisplatin resistance in ovarian cancer. Am J Pathol, 175: 324–333.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Hasan M, Yan N. 2016. Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies. Pharmacol Res, 111: 336–342.CrossRefPubMedGoogle Scholar
  17. Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, Sanjo H, Kawai T, Hoshino K, Takeda K, Akira S. 2004. The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J Exp Med, 199: 1641–1650.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hutti JE, Porter MA, Cheely AW, Cantley LC, Wang X, Kireev D, Baldwin AS, Janzen WP. 2012. Development of a highthroughput assay for identifying inhibitors of TBK1 and IKKepsilon. PLoS One, 7: e41494.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Hutti JE, Shen RR, Abbott DW, Zhou AY, Sprott KM, Asara JM, Hahn WC, Cantley LC. 2009. Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKKepsilon promotes cell transformation. Mol Cell, 34: 461–472.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Johnson EN, Lee YM, Sander TL, Rabkin E, Schoen FJ, Kaushal S, Bischoff J. 2003. NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells. J Biol Chem, 278: 1686–1692.CrossRefPubMedGoogle Scholar
  21. Kaukinen P, Sillanpaa M, Nousiainen L, Melen K, Julkunen I. 2012. Hepatitis C virus NS2 protease inhibits host cell antiviral response by inhibiting IKKepsilon and TBK1 functions. J Med Virol, 85: 71–82.CrossRefPubMedGoogle Scholar
  22. Kiani A, Garcia-Cozar FJ, Habermann I, Laforsch S, Aebischer T, Ehninger G, Rao A. 2001. Regulation of interferon-gamma gene expression by nuclear factor of activated T cells. Blood, 98: 1480–1488.CrossRefPubMedGoogle Scholar
  23. Kim JY, Welsh EA, Oguz U, Fang B, Bai Y, Kinose F, Bronk C, Remsing Rix LL, Beg AA, Rix U, Eschrich SA, Koomen JM, Haura EB. 2013. Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells. Proc Natl Acad Sci U S A, 110: 12414–12419.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Liang D, Gao Y, Lin X, He Z, Zhao Q, Deng Q, Lan K. 2011. A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKepsilon. Cell Res, 21: 793–806.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Liang Q, Fu B, Wu F, Li X, Yuan Y, Zhu F. 2012. ORF45 of Kaposi’s sarcoma-associated herpesvirus inhibits phosphorylation of interferon regulatory factor 7 by IKKepsilon and TBK1 as an alternative substrate. J Virol, 86: 10162–10172.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Lin D, Zhang M, Zhang MX, Ren Y, Jin J, Zhao Q, Pan Z, Wu M, Shu HB, Dong C, Zhong B. 2015. Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6. Proc Natl Acad Sci U S A, 112: 11324–11329.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lu LL, Puri M, Horvath CM, Sen GC. 2008. Select paramyxoviral V proteins inhibit IRF3 activation by acting as alternative substrates for inhibitor of kappaB kinase epsilon (IKKe)/TBK1. J Biol Chem, 283: 14269–14276.CrossRefPubMedPubMedCentralGoogle Scholar
  28. McLaughlin-Drubin ME, Munger K. 2008. Viruses associated with human cancer. Biochim Biophys Acta, 1782: 127–150.CrossRefPubMedGoogle Scholar
  29. McWhirter SM, Fitzgerald KA, Rosains J, Rowe DC, Golenbock DT, Maniatis T. 2004. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc Natl Acad Sci U S A, 101: 233–238.CrossRefPubMedGoogle Scholar
  30. Moore PS, Chang Y. 2010. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat Rev Cancer, 10: 878–889.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Muller MR, Rao A. 2010. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol, 10: 645–656.CrossRefPubMedGoogle Scholar
  32. Peant B, Gilbert S, Le Page C, Poisson A, L’Ecuyer E, Boudhraa Z, Bienz MN, Delvoye N, Saad F, Mes-Masson AM. 2016. IkappaB-Kinase-epsilon (IKKepsilon) over-expression promotes the growth of prostate cancer through the C/EBP-beta dependent activation of IL-6 gene expression. Oncotarget. doi: 10.18632/oncotarget.11629.Google Scholar
  33. Perwitasari O, Cho H, Diamond MS, Gale M, Jr. 2011. Inhibitor of kappaB kinase epsilon (IKK(epsilon)), STAT1, and IFIT2 proteins define novel innate immune effector pathway against West Nile virus infection. J Biol Chem, 286: 44412–44423.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Peters RT, Liao SM, Maniatis T. 2000. IKKepsilon is part of a novel PMA-inducible IkappaB kinase complex. Mol Cell, 5: 513–522.CrossRefPubMedGoogle Scholar
  35. Platanias LC. 2005. Mechanisms of type-I-and type-II-interferonmediated signalling. Nat Rev Immunol, 5: 375–386.CrossRefPubMedGoogle Scholar
  36. Postow MA, Callahan MK, Wolchok JD. 2015. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol, 33: 1974–1982.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Prins KC, Cardenas WB, Basler CF. 2009. Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKepsilon and TBK-1. J Virol, 83: 3069–3077.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Rajsbaum R, Versteeg GA, Schmid S, Maestre AM, Belicha-Villanueva A, Martinez-Romero C, Patel JR, Morrison J, Pisanelli G, Miorin L, Laurent-Rolle M, Moulton HM, Stein DA, Fernandez-Sesma A, tenOever BR, Garcia-Sastre A. 2014. Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKepsilon kinasemediated antiviral response. Immunity, 40: 880–895.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, Rubin JR, Mowers J, White NM, Hochberg I, Downes M, Yu RT, Liddle C, Evans RM, Oh D, Li P, Olefsky JM, Saltiel AR. 2013. An inhibitor of the protein kinases TBK1 and IKK-varepsilon improves obesity-related metabolic dysfunctions in mice. Nat Med, 19: 313–321.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Ren Y, Zhao Y, Lin D, Xu X, Zhu Q, Yao J, Shu HB, Zhong B. 2016. The Type I Interferon-IRF7 Axis Mediates Transcriptional Expression of Usp25 Gene. J Biol Chem, 291: 13206–13215.CrossRefPubMedGoogle Scholar
  41. Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. 2003. Triggering the interferon antiviral response through an IKK-related pathway. Science, 300: 1148–1151.CrossRefPubMedGoogle Scholar
  42. Shen RR, Hahn WC. 2010. Emerging roles for the non-canonical IKKs in cancer. Oncogene, 30: 631–641.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Shimada T, Kawai T, Takeda K, Matsumoto M, Inoue J, Tatsumi Y, Kanamaru A, Akira S. 1999. IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. Int Immunol, 11: 1357–1362.CrossRefPubMedGoogle Scholar
  44. Teijaro JR, Ng C, Lee AM, Sullivan BM, Sheehan KC, Welch M, Schreiber RD, de la Torre JC, Oldstone MB. 2013. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science, 340: 207–211.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Tenoever BR, Ng SL, Chua MA, McWhirter SM, Garcia-Sastre A, Maniatis T. 2007. Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science, 315: 1274–1278.CrossRefPubMedGoogle Scholar
  46. Verhelst K, Verstrepen L, Carpentier I, Beyaert R. 2013. IkappaB kinase epsilon (IKKepsilon): a therapeutic target in inflammation and cancer. Biochem Pharmacol, 85: 873–880.CrossRefPubMedGoogle Scholar
  47. Wang T, Block MA, Cowen S, Davies AM, Devereaux E, Gingipalli L, Johannes J, Larsen NA, Su Q, Tucker JA, Whitston D, Wu J, Zhang HJ, Zinda M, Chuaqui C. 2012. Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKKepsilon kinases. Bioorg Med Chem Lett, 22: 2063–2069.CrossRefPubMedGoogle Scholar
  48. Wang Y, Lu X, Zhu L, Shen Y, Chengedza S, Feng H, Wang L, Jung JU, Gutkind JS, Feng P. 2013. IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis. Proc Natl Acad Sci U S A, 110: 11139–11144.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Wilson EB, Yamada DH, Elsaesser H, Herskovitz J, Deng J, Cheng G, Aronow BJ, Karp CL, Brooks DG. 2013. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science, 340: 202–207.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Wu X, Qi X, Qu B, Zhang Z, Liang M, Li C, Cardona CJ, Li D, Xing Z. 2013. Evasion of antiviral immunity through sequestering of TBK1/IKKepsilon/IRF3 into viral inclusion bodies. J Virol, 88: 3067–3076.CrossRefPubMedGoogle Scholar
  51. Xie X, Zhang D, Zhao B, Lu MK, You M, Condorelli G, Wang CY, Guan KL. 2011. IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A, 108: 6474–6479.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Yu J, Zhou X, Chang M, Nakaya M, Chang JH, Xiao Y, Lindsey JW, Dorta-Estremera S, Cao W, Zal A, Zal T, Sun SC. 2015. Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nat Commun, 6: 6074.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Zeng W, Sun L, Jiang X, Chen X, Hou F, Adhikari A, Xu M, Chen ZJ. 2010. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell, 141: 315–330.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Zhang J, Feng H, Zhao J, Feldman ER, Chen SY, Yuan W, Huang C, Akbari O, Tibbetts SA, Feng P. 2016. IkappaB Kinase epsilon is an NFATc1 kinase that inhibits T cell immune response. Cell Rep, 16: 405–418.CrossRefPubMedGoogle Scholar
  55. Zhao W. 2013. Negative regulation of TBK1-mediated antiviral immunity. FEBS Lett, 587: 542–548.CrossRefPubMedGoogle Scholar
  56. Zitvogel L, Kroemer G. 2012. Targeting PD-1/PD-L1 interactions for cancer immunotherapy. Oncoimmunology, 1: 1223–1225.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Science+Business Media Singapore 2016

Authors and Affiliations

  • Junjie Zhang
    • 1
  • Mao Tian
    • 1
  • Zanxian Xia
    • 2
  • Pinghui Feng
    • 1
  1. 1.Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.State Key Laboratory of Medical Genetics and School of Life SciencesCentral South UniversityChangshaChina

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