Skip to main content

PML Suppresses Influenza Virus Replication by Promoting FBXW7 Expression

Virologica Sinica volume 36, pages 1154–1164 (2021)Cite this article

Abstract

Influenza A viruses (IAV) are responsible for seasonal flu epidemics, which can lead to high morbidity and mortality each year. Like other viruses, influenza virus can hijack host cellular machinery for its replication. Host cells have evolved diverse cellular defense to resist the invasion of viruses. As the main components of promyelocytic leukemia protein nuclear bodies (PML-NBs), PML can inhibit the replication of many medically important viruses including IAV. However, the mechanism of PML against IAV is unclear. In the present study, we found PML was induced in response to IAV infection and ectopic expression of PML could inhibit IAV replication, whereas knockdown of endogenous PML expression could enhance IAV replication. Further studies showed that PML increased the expression of FBXW7 by inhibiting its K48-linked ubiquitination and enhanced the interaction between FBXW7 and SHP2, which negatively regulated IAV replication during infection. Moreover, PML stabilized RIG-I to promote the production of type I IFN. Collectively, these data indicated that PML inhibited IAV replication by enhancing FBXW7 expression in the antiviral immunity against influenza virus and extended the mechanism of PML in antiviral immunity.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  • Alandijany T, Roberts APE, Conn KL, Loney C, McFarlane S, Orr A, Boutell C (2018) Correction: distinct temporal roles for the promyelocytic leukaemia (PML) protein in the sequential regulation of intracellular host immunity to HSV-1 infection. PLoS Pathog 14:e1006927

    Article  Google Scholar 

  • Batty EC, Jensen K, Freemont PS (2012) PML nuclear bodies and other TRIM-defined subcellular compartments. Adv Exp Med Biol 770:39–58

    Article  CAS  Google Scholar 

  • Blondel D, Kheddache S, Lahaye X, Dianoux L, Chelbi-Alix MK (2010) Resistance to rabies virus infection conferred by the PMLIV isoform. J Virol 84:10719–10726

    Article  CAS  Google Scholar 

  • Chang HR, Munkhjargal A, Kim M-J, Park SY, Jung E, Ryu J-H, Yang Y, Lim J-S, Kim Y (2018) The functional roles of PML nuclear bodies in genome maintenance. Mutat Res/fundam Mol Mech Mutagen 809:99–107

    Article  CAS  Google Scholar 

  • Chelbi-Alix MK, Pelicano L, Quignon F, Koken MH, Venturini L, Stadler M, Pavlovic J, Degos L, de Thé H (1995) Induction of the PML protein by interferons in normal and APL cells. Leukemia 9:2027–2033

    CAS  PubMed  Google Scholar 

  • Chelbi-Alix MK, Quignon F, Pelicano L, Koken MH, de Thé H (1998) Resistance to virus infection conferred by the interferon-induced promyelocytic leukemia protein. J Virol 72:1043–1051

    Article  CAS  Google Scholar 

  • Chelbi-Alix MK, Vidy A, El Bougrini J, Blondel D (2006) Rabies viral mechanisms to escape the IFN system: the viral protein P interferes with IRF-3, Stat1, and PML nuclear bodies. J Interferon Cytokine Res 26:271–280

    Article  CAS  Google Scholar 

  • Chen W, Han C, Xie B, Hu X, Yu Q, Shi L, Wang Q, Li D, Wang J, Zheng P, Liu Y, Cao X (2013) Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation. Cell 152:467–478

    Article  CAS  Google Scholar 

  • Chen D, Feng C, Tian X, Zheng N, Wu Z (2018) Promyelocytic leukemia restricts enterovirus 71 replication by inhibiting autophagy. Front Immunol 9:1268

    Article  Google Scholar 

  • El Asmi F, Maroui MA, Dutrieux J, Blondel D, Nisole S, Chelbi-Alix MK (2014) Implication of PMLIV in both intrinsic and innate immunity. PLoS Pathog 10:e1003975

    Article  Google Scholar 

  • Everett RD, Chelbi-Alix MK (2007) PML and PML nuclear bodies: implications in antiviral defence. Biochimie 89:819–830

    Article  CAS  Google Scholar 

  • Giorgi C, Ito K, Lin HK, Santangelo C, Wieckowski MR, Lebiedzinska M, Bononi A, Bonora M, Duszynski J, Bernardi R, Rizzuto R, Tacchetti C, Pinton P, Pandolfi PP (2010) PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330:1247–1251

    Article  CAS  Google Scholar 

  • Hayakawa F, Abe A, Kitabayashi I, Pandolfi PP, Naoe T (2008) Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis. J Biol Chem 283:24420–24425

    Article  CAS  Google Scholar 

  • Hsu KS, Kao HY (2018) PML: regulation and multifaceted function beyond tumor suppression. Cell Biosci 8:5

    Article  Google Scholar 

  • Iki S, Yokota S, Okabayashi T, Yokosawa N, Nagata K, Fujii N (2005) Serum-dependent expression of promyelocytic leukemia protein suppresses propagation of influenza virus. Virology 343:106–115

    Article  CAS  Google Scholar 

  • Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW, Xiao Y, Christie AL, Aster J, Settleman J, Gygi SP, Kung AL, Look T, Nakayama KI, DePinho RA, Wei W (2011) SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471:104–109

    Article  CAS  Google Scholar 

  • Janer A, Martin E, Muriel MP, Latouche M, Fujigasaki H, Ruberg M, Brice A, Trottier Y, Sittler A (2006) PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins. J Cell Biol 174:65–76

    Article  CAS  Google Scholar 

  • Kell AM, Gale M Jr (2015) RIG-I in RNA virus recognition. Virology 479–480:110–121

    Article  Google Scholar 

  • Kentsis A, Dwyer EC, Perez JM, Sharma M, Chen A, Pan ZQ, Borden KL (2001) The RING domains of the promyelocytic leukemia protein PML and the arenaviral protein Z repress translation by directly inhibiting translation initiation factor eIF4E. J Mol Biol 312:609–623

    Article  CAS  Google Scholar 

  • Krammer F, Palese P (2015) Advances in the development of influenza virus vaccines. Nat Rev Drug Discov 14:167–182

    Article  CAS  Google Scholar 

  • Li W, Wang G, Zhang H, Zhang D, Zeng J, Chen X, Xu Y, Li K (2009) Differential suppressive effect of promyelocytic leukemia protein on the replication of different subtypes/strains of influenza A virus. Biochem Biophys Res Commun 389:84–89

    Article  CAS  Google Scholar 

  • Li K, Wang F, Cao WB, Lv XX, Hua F, Cui B, Yu JJ, Zhang XW, Shang S, Liu SS, Yu JM, Han MZ, Huang B, Zhang TT, Li X, Jiang JD, Hu ZW (2017) TRIB3 promotes APL progression through stabilization of the oncoprotein PML-RARα and inhibition of p53-mediated senescence. Cancer Cell 31:697-710.e697

    Article  CAS  Google Scholar 

  • Lin HK, Bergmann S, Pandolfi PP (2004) Cytoplasmic PML function in TGF-beta signalling. Nature 431:205–211

    Article  CAS  Google Scholar 

  • Maul GG, Guldner HH, Spivack JG (1993) Modification of discrete nuclear domains induced by herpes simplex virus type 1 immediate early gene 1 product (ICP0). J Gen Virol 74:2679–2690

    Article  CAS  Google Scholar 

  • Moberg KH, Bell DW, Wahrer DC, Haber DA, Hariharan IK (2001) Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413:311–316

    Article  CAS  Google Scholar 

  • Negorev D, Maul GG (2001) Cellular proteins localized at and interacting within ND10/PML nuclear bodies/PODs suggest functions of a nuclear depot. Oncogene 20:7234–7242

    Article  CAS  Google Scholar 

  • Nisole S, Stoye JP, Saïb A (2005) TRIM family proteins: retroviral restriction and antiviral defence. Nat Rev Microbiol 3:799–808

    Article  CAS  Google Scholar 

  • Nisole S, Maroui MA, Mascle XH, Aubry M, Chelbi-Alix MK (2013) Differential roles of PML isoforms. Front Oncol 3:125

    Article  Google Scholar 

  • Reineke EL, Lam M, Liu Q, Liu Y, Stanya KJ, Chang KS, Means AR, Kao HY (2008) Degradation of the tumor suppressor PML by Pin1 contributes to the cancer phenotype of breast cancer MDA-MB-231 cells. Mol Cell Biol 28:997–1006

    Article  CAS  Google Scholar 

  • Scherer M, Stamminger T (2016) Emerging role of PML nuclear bodies in innate immune signaling. J Virol 90:5850–5854

    Article  CAS  Google Scholar 

  • Shaw ML, Stertz S (2018) Role of host genes in influenza virus replication. Curr Top Microbiol Immunol 419:151–189

    CAS  PubMed  Google Scholar 

  • Song Y, Lai L, Chong Z, He J, Zhang Y, Xue Y, Xie Y, Chen S, Dong P, Chen L, Chen Z, Dai F, Wan X, Xiao P, Cao X, Liu Y, Wang Q (2017) E3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses. Nat Commun 8:14654

    Article  CAS  Google Scholar 

  • Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N, Hatakeyama S, Bessho Y, Kageyama R, Suda T, Nakayama KI (2004) Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. J Biol Chem 279:9417–9423

    Article  CAS  Google Scholar 

  • Wang R, Wang Y, Liu N, Ren C, Jiang C, Zhang K, Yu S, Chen Y, Tang H, Deng Q, Fu C, Wang Y, Li R, Liu M, Pan W, Wang P (2013) FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation. Cell Res 23:803–819

    Article  Google Scholar 

  • Wang G, Tian Y, Hu Q, Xiao X, Chen S (2018) PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms. J Cell Biochem. https://doi.org/10.1002/jcb.27077

    Article  PubMed  PubMed Central  Google Scholar 

  • Welcker M, Clurman BE (2008) FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer 8:83–93

    Article  CAS  Google Scholar 

  • Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, Ishida N, Okumura F, Nakayama K, Nakayama KI (2004) Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. Embo J 23:2116–2125

    Article  CAS  Google Scholar 

  • Zhong S, Hu P, Ye TZ, Stan R, Ellis NA, Pandolfi PP (1999) A role for PML and the nuclear body in genomic stability. Oncogene 18:7941–7947

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was financially supported by National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2018ZX09711003), CAMS Initiative for Innovative Medicine (CAMS-I2M-1-010), and National Natural Science Foundation of China (81630089).

Author information

Authors and Affiliations

  1. CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Hai-Yan Yan, Hui-Qiang Wang, Ming Zhong, Shuo Wu, Lu Yang & Yu-Huan Li

  2. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Hai-Yan Yan, Hui-Qiang Wang, Ming Zhong, Shuo Wu, Lu Yang & Yu-Huan Li

  3. NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, 100050, China

    Ke Li

Authors
  1. Hai-Yan Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui-Qiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuo Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ke Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu-Huan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HYY, KL and YHL designed the experiments. HYY and MZ carried out the experiments. HYY, MZ and LY analyzed the data. HYY, HQW, and SW wrote the manuscript. KL and YHL finalized the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ke Li or Yu-Huan Li.

Ethics declarations

Conflict of interest

No potential conflict of interest was reported by the authors.

Animal and Human Rights Statement

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 107 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yan, HY., Wang, HQ., Zhong, M. et al. PML Suppresses Influenza Virus Replication by Promoting FBXW7 Expression. Virol. Sin. 36, 1154–1164 (2021). https://doi.org/10.1007/s12250-021-00399-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12250-021-00399-3

Keywords

  • Influenza A virus (IAV)
  • Promyelocytic leukemia (PML)
  • FBXW7
  • RIG-I