Skip to main content
SpringerLink
Log in

Sec13 is a positive regulator of VISA-mediated antiviral signaling

  • Published:
Virus Genes Aims and scope Submit manuscript

Abstract

Viral infection triggers the innate antiviral immune response that rapidly produces type I interferons in most cell types to combat viruses invading. Upon viral infection, the cytoplasmic RNA sensors RIG-I/MDA5 recognize viral RNA, and then RIG-I/MDA5 is transported to mitochondria interacting with VISA through the CARD domain. From there, VISA recruits downstream antiviral signaling pathways molecules, such as TRAFs and TBK1. Eventually, IRF3 is phosphorylated and type I IFNs are induced to fight as the first line of defense against viruses. However, it remains unclear how VISA acts as a scaffold to assemble the signalosome in RIG-I-mediated antiviral signaling. Here, we demonstrated Sec13 as a novel component that was involved in VISA-mediated antiviral signaling pathway. The co-immunoprecipitation assays showed that Sec13 specifically interacts with VISA. Overexpression of Sec13 increases VISA’s aggregation and ubiquitination and significantly enhances the phosphorylation and dimerization of IRF3, facilitating the IFN-β production. Conversely, the knockdown of Sec13 attenuates Sendai virus-induced and VISA-mediated IRF3 activation and the production of IFNβ, thus weakens antiviral immune activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. V. Hornung, J. Ellegast, S. Kim, K. Brzozka, A. Jung, H. Kato, H. Poeck, S. Akira, K.K. Conzelmann, M. Schlee, S. Endres, G. Hartmann, 5′-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006)

    Article  PubMed  Google Scholar 

  2. O. Takeuchi, S. Akira, Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010)

    Article  PubMed  CAS  Google Scholar 

  3. B. Beutler, Z. Jiang, P. Georgel, K. Crozat, B. Croker, S. Rutschmann, X. Du, K. Hoebe, Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24, 353–389 (2006)

    Article  PubMed  CAS  Google Scholar 

  4. M. Yoneyama, T. Fujita, Structural mechanism of RNA recognition by the RIG-I-like receptors. Immunity 29, 178–181 (2008)

    Article  PubMed  CAS  Google Scholar 

  5. O. Takeuchi, S. Akira, Innate immunity to virus infection. Immunol. Rev. 227, 75–86 (2009)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. M. Yoneyama, M. Kikuchi, T. Natsukawa, N. Shinobu, T. Imaizumi, M. Miyagishi, K. Taira, S. Akira, T. Fujita, The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004)

    Article  PubMed  CAS  Google Scholar 

  7. M.U. Gack, Y.C. Shin, C.H. Joo, T. Urano, C. Liang, L. Sun, O. Takeuchi, S. Akira, Z. Chen, S. Inoue, J.U. Jung, TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916–920 (2007)

    Article  PubMed  CAS  Google Scholar 

  8. A. Pichlmair, O. Schulz, C.P. Tan, T.I. Naslund, P. Liljestrom, F. Weber, C. Reis e Sousa, RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314, 997–1001 (2006)

    Article  PubMed  CAS  Google Scholar 

  9. F. Ferrage, K. Dutta, E. Nistal-Villan, J.R. Patel, M.T. Sanchez-Aparicio, P. De Ioannes, A. Buku, G.G. Aseguinolaza, A. Garcia-Sastre, A.K. Aggarwal, Structure and dynamics of the second CARD of human RIG-I provide mechanistic insights into regulation of RIG-I activation. Structure 20, 2048–2061 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. L.G. Xu, Y.Y. Wang, K.J. Han, L.Y. Li, Z. Zhai, H.B. Shu, VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19, 727–740 (2005)

    Article  PubMed  CAS  Google Scholar 

  11. R.B. Seth, L. Sun, C.K. Ea, Z.J. Chen, Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669–682 (2005)

    Article  PubMed  CAS  Google Scholar 

  12. T. Kawai, K. Takahashi, S. Sato, C. Coban, H. Kumar, H. Kato, K.J. Ishii, O. Takeuchi, S. Akira, IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6, 981–988 (2005)

    Article  PubMed  CAS  Google Scholar 

  13. E. Dixit, S. Boulant, Y. Zhang, A.S. Lee, C. Odendall, B. Shum, N. Hacohen, Z.J. Chen, S.P. Whelan, M. Fransen, M.L. Nibert, G. Superti-Furga, J.C. Kagan, Peroxisomes are signaling platforms for antiviral innate immunity. Cell 141, 668–681 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. S.M. Horner, H.M. Liu, H.S. Park, J. Briley, M. Gale Jr., Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus. Proc. Natl. Acad. Sci. USA 108, 14590–14595 (2011)

    Article  PubMed  CAS  Google Scholar 

  15. J.L. Jacobs, C.B. Coyne, Mechanisms of MAVS regulation at the mitochondrial membrane. J. Mol. Biol. 425, 5009–5019 (2013)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. S.K. Saha, E.M. Pietras, J.Q. He, J.R. Kang, S.Y. Liu, G. Oganesyan, A. Shahangian, B. Zarnegar, T.L. Shiba, Y. Wang, G. Cheng, Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J. 25, 3257–3263 (2006)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. C. Vazquez, S.M. Horner, MAVS coordination of antiviral innate immunity. J. Virol. 89, 6974–6977 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. F. Hou, L. Sun, H. Zheng, B. Skaug, Q.X. Jiang, Z.J. Chen, MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448–461 (2011)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. E.D. Tang, C.Y. Wang, MAVS self-association mediates antiviral innate immune signaling. J. Virol. 83, 3420–3428 (2009)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. J.Q. He, G. Oganesyan, S.K. Saha, B. Zarnegar, G. Cheng, TRAF3 and its biological function. Adv. Exp. Med. Biol. 597, 48–59 (2007)

    Article  PubMed  Google Scholar 

  21. S. Paz, Q. Sun, P. Nakhaei, R. Romieu-Mourez, D. Goubau, I. Julkunen, R. Lin, J. Hiscott, Induction of IRF-3 and IRF-7 phosphorylation following activation of the RIG-I pathway. Cell. Mol. Biol. (Noisy-le-grand) 52, 17–28 (2006)

    CAS  Google Scholar 

  22. K.A. Fitzgerald, S.M. McWhirter, K.L. Faia, D.C. Rowe, E. Latz, D.T. Golenbock, A.J. Coyle, S.M. Liao, T. Maniatis, IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4, 491–496 (2003)

    Article  PubMed  CAS  Google Scholar 

  23. S. Paz, M. Vilasco, S.J. Werden, M. Arguello, D. Joseph-Pillai, T. Zhao, T.L. Nguyen, Q. Sun, E.F. Meurs, R. Lin, J. Hiscott, A functional C-terminal TRAF3-binding site in MAVS participates in positive and negative regulation of the IFN antiviral response. Cell Res. 21, 895–910 (2011)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. S. Vallabhapurapu, M. Karin, Regulation and function of NF-kappaB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009)

    Article  PubMed  CAS  Google Scholar 

  25. S. Alberti, R. Halfmann, O. King, A. Kapila, S. Lindquist, A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137, 146–158 (2009)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. D. Vitour, S. Dabo, M. Ahmadi Pour, M. Vilasco, P.O. Vidalain, Y. Jacob, M. Mezel-Lemoine, S. Paz, M. Arguello, R. Lin, F. Tangy, J. Hiscott, E.F. Meurs, Polo-like kinase 1 (PLK1) regulates interferon (IFN) induction by MAVS. J. Biol. Chem. 284, 21797–21809 (2009)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. B. Wu, S. Hur, How RIG-I like receptors activate MAVS. Curr. Opin. Virol. 12, 91–98 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. B. Zhong, Y. Zhang, B. Tan, T.T. Liu, Y.Y. Wang, H.B. Shu, The E3 ubiquitin ligase RNF5 targets virus-induced signaling adaptor for ubiquitination and degradation. J. Immunol. 184, 6249–6255 (2010)

    Article  PubMed  CAS  Google Scholar 

  29. Y. Wang, X. Tong, X. Ye, Ndfip1 negatively regulates RIG-I-dependent immune signaling by enhancing E3 ligase Smurf1-mediated MAVS degradation. J. Immunol. 189, 5304–5313 (2012)

    Article  PubMed  CAS  Google Scholar 

  30. Y. Pan, R. Li, J.L. Meng, H.T. Mao, Y. Zhang, J. Zhang, Smurf2 negatively modulates RIG-I-dependent antiviral response by targeting VISA/MAVS for ubiquitination and degradation. J. Immunol. 192, 4758–4764 (2014)

    Article  PubMed  CAS  Google Scholar 

  31. F. You, H. Sun, X. Zhou, W. Sun, S. Liang, Z. Zhai, Z. Jiang, PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat. Immunol. 10, 1300–1308 (2009)

    Article  PubMed  CAS  Google Scholar 

  32. X. Zhou, F. You, H. Chen, Z. Jiang, Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS). Cell Res. 22, 717–727 (2012)

    Article  PubMed  CAS  Google Scholar 

  33. K. Arimoto, H. Takahashi, T. Hishiki, H. Konishi, T. Fujita, K. Shimotohno, Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc. Natl. Acad. Sci. USA 104, 7500–7505 (2007)

    Article  PubMed  CAS  Google Scholar 

  34. Y.S. Yoo, Y.Y. Park, J.H. Kim, H. Cho, S.H. Kim, H.S. Lee, T.H. Kim, Y. Sun Kim, Y. Lee, C.J. Kim, J.U. Jung, J.S. Lee, H. Cho, The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling. Nat. Commun. 6, 7910 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. C. Castanier, N. Zemirli, A. Portier, D. Garcin, N. Bidere, A. Vazquez, D. Arnoult, MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors. BMC Biol. 10, 44 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. B. Lin, Q. Ke, H. Li, N.S. Pheifer, D.C. Velliquette, D.W. Leaman, Negative regulation of the RLH signaling by the E3 ubiquitin ligase RNF114. Cytokine 99, 186–193 (2017)

    Article  PubMed  CAS  Google Scholar 

  37. J.L. Jacobs, J. Zhu, S.N. Sarkar, C.B. Coyne, Regulation of mitochondrial antiviral signaling (MAVS) expression and signaling by the mitochondria-associated endoplasmic reticulum membrane (MAM) protein Gp78. J. Biol. Chem. 289, 1604–1616 (2014)

    Article  PubMed  CAS  Google Scholar 

  38. Q. Wang, X. Liu, Y. Cui, Y. Tang, W. Chen, S. Li, H. Yu, Y. Pan, C. Wang, The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING. Immunity 41, 919–933 (2014)

    Article  PubMed  CAS  Google Scholar 

  39. W.W. Luo, S. Li, C. Li, Z.Q. Zheng, P. Cao, Z. Tong, H. Lian, S.Y. Wang, H.B. Shu, Y.Y. Wang, iRhom2 is essential for innate immunity to RNA virus by antagonizing ER- and mitochondria-associated degradation of VISA. PLoS Pathog. 13, e1006693 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. C. Barlowe, L. Orci, T. Yeung, M. Hosobuchi, S. Hamamoto, N. Salama, M.F. Rexach, M. Ravazzola, M. Amherdt, R. Schekman, COPII: a membrane coat formed by Sec proteins that drive vesicle budding from the endoplasmic reticulum. Cell 77, 895–907 (1994)

    Article  PubMed  CAS  Google Scholar 

  41. J. Enninga, A. Levay, B.M.A. Fontoura, Sec13 shuttles between the nucleus and the cytoplasm and stably interacts with Nup96 at the nuclear pore complex. Mol. Cell. Biol. 23 (2003) 7271–7284

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. N.R. Salama, T. Yeung, R.W. Schekman, The Sec13p complex and reconstitution of vesicle budding from the ER with purified cytosolic proteins. EMBO J 12, 4073–4082 (1993)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. L. Fu, E. Sztul, Traffic-independent function of the Sar1p/COPII machinery in proteasomal sorting of the cystic fibrosis transmembrane conductance regulator. J. Cell Biol. 160, 157–163 (2003)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. V. Haucke, Vesicle budding: a coat for the COPs. Trends Cell Biol. 13, 59–60 (2003)

    Article  PubMed  CAS  Google Scholar 

  45. S.M. Stagg, C. Gurkan, D.M. Fowler, P. LaPointe, T.R. Foss, C.S. Potter, B. Carragher, W.E. Balch, Structure of the Sec13/31 COPII coat cage. Nature 439, 234–238 (2006)

    Article  PubMed  CAS  Google Scholar 

  46. S.M. Stagg, P. LaPointe, A. Razvi, C. Gurkan, C.S. Potter, B. Carragher, W.E. Balch, Structural basis for cargo regulation of COPII coat assembly. Cell 134, 474–484 (2008)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. K. Matsuoka, L. Orci, M. Amherdt, S.Y. Bednarek, S. Hamamoto, R. Schekman, T. Yeung, COPII-coated vesicle formation reconstituted with purified coat proteins and chemically defined liposomes. Cell 93, 263–275 (1998)

    Article  PubMed  CAS  Google Scholar 

  48. L. Ellgaard, A. Helenius, ER quality control: towards an understanding at the molecular level. Curr. Opin. Cell Biol. 13, 431–437 (2001)

    Article  PubMed  CAS  Google Scholar 

  49. J.L. Brodsky, A.A. McCracken, ER protein quality control and proteasome-mediated protein degradation. Semin. Cell Dev. Biol. 10, 507–513 (1999)

    Article  PubMed  CAS  Google Scholar 

  50. K. Bienz, D. Egger, T. Pfister, Characteristics of the poliovirus replication complex. Arch. Virol. Suppl. 9, 147–157 (1994)

    PubMed  CAS  Google Scholar 

  51. R.C. Rust, L. Landmann, R. Gosert, B.L. Tang, W. Hong, H.P. Hauri, D. Egger, K. Bienz, Cellular COPII proteins are involved in production of the vesicles that form the poliovirus replication complex. J. Virol. 75, 9808–9818 (2001)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. J. Enninga, A. Levay, B.M. Fontoura, Sec13 shuttles between the nucleus and the cytoplasm and stably interacts with Nup96 at the nuclear pore complex. Mol. Cell. Biol. 23, 7271–7284 (2003)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. J. Enninga, D.E. Levy, G. Blobel, B.M. Fontoura, Role of nucleoporin induction in releasing an mRNA nuclear export block. Science 295, 1523–1525 (2002)

    Article  PubMed  CAS  Google Scholar 

  54. C. von Kobbe, J.M. van Deursen, J.P. Rodrigues, D. Sitterlin, A. Bachi, X. Wu, M. Wilm, M. Carmo-Fonseca, E. Izaurralde, Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98. Mol. Cell 6, 1243–1252 (2000)

    Article  PubMed  CAS  Google Scholar 

  55. M. Ahmed, D.S. Lyles, Effect of vesicular stomatitis virus matrix protein on transcription directed by host RNA polymerases I, II, and III. J. Virol. 72, 8413–8419 (1998)

    PubMed  PubMed Central  CAS  Google Scholar 

  56. M. Capelson, Y. Liang, R. Schulte, W. Mair, U. Wagner, M.W. Hetzer, Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes. Cell 140, 372–383 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. X. Niu, J. Hong, X. Zheng, D.B. Melville, E.W. Knapik, A. Meng, J. Peng, The nuclear pore complex function of Sec13 protein is required for cell survival during retinal development. J. Biol. Chem. 289, 11971–11985 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. J. Zhu, T. Davoli, J.M. Perriera, C.R. Chin, G.D. Gaiha, S.P. John, F.D. Sigiollot, G. Gao, Q. Xu, H. Qu, T. Pertel, J.S. Sims, J.A. Smith, R.E. Baker, L. Maranda, A. Ng, S.J. Elledge, A.L. Brass, Comprehensive identification of host modulators of HIV-1 replication using multiple orthologous RNAi reagents. Cell Rep. 9, 752–766 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. T.G. Moreira, L. Zhang, L. Shaulov, A. Harel, S.K. Kuss, J. Williams, J. Shelton, B. Somatilaka, J. Seemann, J. Yang, R. Sakthivel, D.R. Nussenzveig, A.M. Faria, B.M. Fontoura, Sec13 regulates expression of specific immune factors involved in inflammation in vivo. Sci Rep. 5, 17655 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr. Hong-Bing Shu (Medical Research Institute, Wuhan University) for his helping for providing plasmids and other reagents assistance. This work was supported by Grants from the National Natural Science Foundation of China (Grant Nos. 31370876, 31570876), the Natural Science Foundation of Jiangxi Province (20143ACB20004, 20161BAB204177), the Open Project Program of Key Laboratory of Functional Small Organic Molecule, Ministry of Education, and Jiangxi Normal University (KLFS-KF-201407), Postdoctoral Start Fund of Jiangxi Normal University (2014A).

Author information

Authors and Affiliations

  1. Key Laboratory of Functional Small Organic Molecule, Ministry of Education and College of Life Science, Jiangxi Normal University, 99 Ziyang Road, Nanchang, 330022, Jiangxi, China

    Tian Chen, Dandan Wang, Tao Xie & Liang-Guo Xu

Authors
  1. Tian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dandan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tao Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang-Guo Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LX designed the research. TC, TX, and DW performed the experiments. LX and TC did data analysis and discussion. TC and LX wrote the manuscript.

Corresponding author

Correspondence to Liang-Guo Xu.

Ethics declarations

Conflict of interest

The author declares no conflict of interest.

Human and animal participants

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Edited by Hartmut Hengel.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, T., Wang, D., Xie, T. et al. Sec13 is a positive regulator of VISA-mediated antiviral signaling. Virus Genes 54, 514–526 (2018). https://doi.org/10.1007/s11262-018-1581-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11262-018-1581-0

Keywords

Search

Navigation