Skip to main content
SpringerLink
Log in

SRP54 Negatively Regulates IFN-Beta Production and Antiviral Response by Targeting RIG-I and MDA5

  • RESEARCH ARTICLE
  • Published:
Virologica Sinica

Abstract

During virus infection, RIG-I-like receptors (RLRs) recognize viral RNAs and recruit the adaptor protein VISA to activate downstream signaling, leading to activation of transcription factors NF-κB and IRF3, which collaborate to induce type I interferons (IFNs). IFNs further induce expression of hundreds of IFN-stimulated genes (ISGs) that suppress viral replication and facilitate the adaptive immune response. Dysregulated production of IFNs is implicated in various immune diseases. Here we identified Signal Recognition Particle 54 (SRP54) as a negative regulator of RLRs-induced antiviral signaling. Overexpression of SRP54 inhibited RNA virus-triggered induction of IFN-β and increased viral replication, whereas knockdown of SRP54 had opposite effects. Mechanistically, SRP54 interacted with both RIG-I and MDA5 and impaired their association with VISA. Our findings demonstrate that SRP54 acts as a negative regulator of RLRs-mediated innate immune response by disrupting the recruitment of VISA to RIG-I/MDA5.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    Article  CAS  Google Scholar 

  • Akopian D, Shen K, Zhang X, Shan SO (2013) Signal recognition particle: an essential protein-targeting machine. Annu Rev Biochem 82:693–721

    Article  CAS  Google Scholar 

  • Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded rna and activation of nf-κb by toll-like receptor 3. Nature 413:732–738

    Article  CAS  Google Scholar 

  • Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, Goodbourn S, Randall RE (2004) The v proteins of paramyxoviruses bind the ifn-inducible rna helicase, mda-5, and inhibit its activation of the ifn-beta promoter. Proc Natl Acad Sci USA 101:17264–17269

    Article  CAS  Google Scholar 

  • Bacher G, Lütcke H, Jungnickel B, Rapoport TA, Dobberstein B (1996) Regulation by the ribosome of the gtpase of the signal-recognition particle during protein targeting. Nature 381:248–251

    Article  CAS  Google Scholar 

  • Bellanné-Chantelot C, Schmaltz-Panneau B, Marty C, Fenneteau O, Callebaut I, Clauin S, Docet A, Damaj G-L, Leblanc T, Pellier I, Stoven C, Souquere S, Antony-Debré I, Beaupain B, Aladjidi N, Barlogis V, Bauduer F, Bensaid P, Boespflug-Tanguy O, Berger C, Bertrand Y, Carausu L, Fieschi C, Galambrun C, Schmidt A, Journel H, Mazingue F, Nelken B, Quah TC, Oksenhendler E, Ouachée M, Pasquet M, Saada V, Suarez F, Pierron G, Vainchenker W, Plo I, Donadieu J (2018) Mutations in the srp54 gene cause severe congenital neutropenia as well as shwachman-diamond-like syndrome. Blood 132:1318–1331

    Article  Google Scholar 

  • Cao X (2016) Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat Rev Immunol 16:35–50

    Article  CAS  Google Scholar 

  • Carapito R, Konantz M, Paillard C, Miao Z, Pichot A, Leduc MS, Yang Y, Bergstrom KL, Mahoney DH, Shardy DL, Alsaleh G, Naegely L, Kolmer A, Paul N, Hanauer A, Rolli V, Muller JS, Alghisi E, Sauteur L, Macquin C, Morlon A, Sancho CS, Amati-Bonneau P, Procaccio V, Mosca-Boidron AL, Marle N, Osmani N, Lefebvre O, Goetz JG, Unal S, Akarsu NA, Radosavljevic M, Chenard MP, Rialland F, Grain A, Bene MC, Eveillard M, Vincent M, Guy J, Faivre L, Thauvin-Robinet C, Thevenon J, Myers K, Fleming MD, Shimamura A, Bottollier-Lemallaz E, Westhof E, Lengerke C, Isidor B, Bahram S (2017) Mutations in signal recognition particle srp54 cause syndromic neutropenia with shwachman-diamond-like features. J Clin Invest 127:4090–4103

    Article  Google Scholar 

  • Carty M, Kearney J, Shanahan KA, Hams E, Sugisawa R, Connolly D, Doran CG, Munoz-Wolf N, Gurtler C, Fitzgerald KA, Lavelle EC, Fallon PG, Bowie AG (2019) Cell survival and cytokine release after inflammasome activation is regulated by the toll-il-1r protein sarm. Immunity 50(6):1412–1424

    Article  CAS  Google Scholar 

  • Egea PF, Stroud RM, Walter P (2005) Targeting proteins to membranes: structure of the signal recognition particle. Curr Opin Struct Biol 15:213–220

    Article  CAS  Google Scholar 

  • Focia PJ, Shepotinovskaya IV, Seidler JA, Freymann DM (2004) Heterodimeric gtpase core of the srp targeting complex. Science 303:373–377

    Article  CAS  Google Scholar 

  • Freymann DM, Keenan RJ, Stroud RM, Walter P (1997) Structure of the conserved gtpase domain of the signal recognition particle. Nature 385:361–364

    Article  CAS  Google Scholar 

  • Honda K, Takaoka A, Taniguchi T (2006) Type i interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 25:349–360

    Article  CAS  Google Scholar 

  • Hu MM, Liao CY, Yang Q, Xie XQ, Shu HB (2017) Innate immunity to rna virus is regulated by temporal and reversible sumoylation of rig-i and mda5. J Exp Med 214:973–989

    Article  CAS  Google Scholar 

  • Janda CY, Li J, Oubridge C, Hernández H, Robinson CV, Nagai K (2010) Recognition of a signal peptide by the signal recognition particle. Nature 465:507–510

    Article  CAS  Google Scholar 

  • Kowalinski E, Lunardi T, McCarthy AA, Louber J, Brunel J, Grigorov B, Gerlier D, Cusack S (2011) Structural basis for the activation of innate immune pattern-recognition receptor rig-i by viral RNA. Cell 147:423–435

    Article  CAS  Google Scholar 

  • Kurita K, Honda K, Suzuma S, Takamatsu H, Nakamura K, Yamane K (1996) Identification of a region of bacillus subtilis FFH, a homologue of mammalian SRP54 protein, that is essential for binding to small cytoplasmic RNA. J Biol Chem 271:13140–13146

    Article  CAS  Google Scholar 

  • Lei CQ, Zhang Y, Li M, Jiang LQ, Zhong B, Kim YH, Shu HB (2015) Ecsit bridges rig-i-like receptors to visa in signaling events of innate antiviral responses. J Innate Immun 7:153–164

    Article  CAS  Google Scholar 

  • Lian H, Zang R, Wei J, Ye W, Hu M-M, Chen Y-D, Zhang X-N, Guo Y, Lei C-Q, Yang Q, Luo W-W, Li S, Shu H-B (2018) The zinc-finger protein zcchc3 binds rna and facilitates viral rna sensing and activation of the rig-i-like receptors. Immunity 49:438–448.e435

    Article  CAS  Google Scholar 

  • Luirink J, Dobberstein B (1994) Mammalian and escherichia coli signal recognition particles. Mol Microbiol 11:9–13

    Article  CAS  Google Scholar 

  • Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the rig-i antiviral pathway and is targeted by hepatitis c virus. Nature 437:1167–1172

    Article  CAS  Google Scholar 

  • Randall RE, Goodbourn S (2008) Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 89:1–47

    Article  CAS  Google Scholar 

  • Roers A, Hiller B, Hornung V (2016) Recognition of endogenous nucleic acids by the innate immune system. Immunity 44:739–754

    Article  CAS  Google Scholar 

  • Samuelsson T (1992) A mycoplasma protein homologous to mammalian SRP54 recognizes a highly conserved domain of SRP RNA. Nucleic Acids Res 20:5763–5770

    Article  CAS  Google Scholar 

  • Seth RB, Sun L, Ea CK, Chen ZJ (2005) Identification and characterization of mavs, a mitochondrial antiviral signaling protein that activates nf-kappab and irf 3. Cell 122:669–682

    Article  CAS  Google Scholar 

  • Watanabe Y, Uruha A, Suzuki S, Nakahara J, Hamanaka K, Takayama K, Suzuki N, Nishino I (2016) Clinical features and prognosis in anti-srp and anti-hmgcr necrotising myopathy. J Neurol Neurosurg Psychiatry 87:1038–1044

    Article  Google Scholar 

  • Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB (2005) Visa is an adapter protein required for virus-triggered ifn-beta signaling. Mol Cell 19:727–740

    Article  CAS  Google Scholar 

  • Yang Y, Wang SY, Huang ZF, Zou HM, Yan BR, Luo WW, Wang YY (2016) The rna-binding protein mex3b is a coreceptor of toll-like receptor 3 in innate antiviral response. Cell Res 26:288–303

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, Lei C, He X, Zhang L, Tien P, Shu HB (2008) The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29:538–550

    Article  CAS  Google Scholar 

  • Zopf D, Bernstein HD, Johnson AE, Walter P (1990) The methionine-rich domain of the 54 kd protein subunit of the signal recognition particle contains an rna binding site and can be crosslinked to a signal sequence. EMBO J 9:4511–4517

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (31770946, awarded to Y.Y.) and Key Research Programs of Frontier Science (awarded to Y.Y.W.) funded by Chinese Academy of Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China

    Dong-Peng Wang, Hong-Yan Zhang, Bo-Wei Liao, Zhen Tong, Zhi-Sheng Xu, Yan-Yi Wang & Yan Yang

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Dong-Peng Wang, Hong-Yan Zhang, Bo-Wei Liao & Zhen Tong

Authors
  1. Dong-Peng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong-Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bo-Wei Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhen Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhi-Sheng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yan-Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DPW, YYW and YY designed the experiments. DPW, HYZ, BWL and TZ carried out the experiments. DPW, ZSX, YYW and YY analyzed the data. DPW wrote the paper. YY and YYW checked and finalized the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yan-Yi Wang or Yan Yang.

Ethics declarations

Conflict of interest

The authors declare that they no conflict interest.

Animal and Human Rights Statement

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, DP., Zhang, HY., Liao, BW. et al. SRP54 Negatively Regulates IFN-Beta Production and Antiviral Response by Targeting RIG-I and MDA5. Virol. Sin. 36, 231–240 (2021). https://doi.org/10.1007/s12250-020-00267-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12250-020-00267-6

Keywords

Search

Navigation