Top

Published in:

Open Access 01-12-2022 | Influenza | Research

Tripartite motif-containing protein 46 accelerates influenza A H7N9 virus infection by promoting K48-linked ubiquitination of TBK1

Authors: Wei Su, Xian-Tian Lin, Shuai Zhao, Xiao-Qin Zheng, Yu-Qing Zhou, Lan-Lan Xiao, Hui Chen, Zheng-Yu Zhang, Li-Jun Zhang, Xiao-Xin Wu

Published in: Virology Journal | Issue 1/2022

Abstract

Background

Avian influenza A H7N9 emerged in 2013, threatening public health and causing acute respiratory distress syndrome, and even death, in the human population. However, the underlying mechanism by which H7N9 virus causes human infection remains elusive.

Methods

Herein, we infected A549 cells with H7N9 virus for different times and assessed tripartite motif-containing protein 46 (TRIM46) expression. To determine the role of TRIM46 in H7N9 infection, we applied lentivirus-based TRIM46 short hairpin RNA sequences and overexpression plasmids to explore virus replication, and changes in type I interferons and interferon regulatory factor 3 (IRF3) phosphorylation levels in response to silencing and overexpression of TRIM46. Finally, we used Co-immunoprecipitation and ubiquitination assays to examine the mechanism by which TRIM46 mediated the activity of TANK-binding kinase 1 (TBK1).

Results

Type I interferons play an important role in defending virus infection. Here, we found that TRIM46 levels were significantly increased during H7N9 virus infection. Furthermore, TRIM46 knockdown inhibited H7N9 virus replication compared to that in the control group, while the production of type I interferons increased. Meanwhile, overexpression of TRIM46 promoted H7N9 virus replication and decrease the production of type I interferons. In addition, the level of phosphorylated IRF3, an important interferon regulatory factor, was increased in TRIM46-silenced cells, but decreased in TRIM46 overexpressing cells. Mechanistically, we observed that TRIM46 could interact with TBK1 to induce its K48-linked ubiquitination, which promoted H7N9 virus infection.

Conclusion

Our results suggest that TRIM46 negatively regulates the human innate immune response against H7N9 virus infection.

Available only for authorised users

Liu WJ, Xiao H, Dai L, Liu D, Chen J, Qi X, et al. Avian influenza A (H7N9) virus: from low pathogenic to highly pathogenic. Front Med. 2021;15(4):507–27.PubMedPubMedCentralCrossRef

Su S, Gu M, Liu D, Cui J, Gao GF, Zhou J, et al. Epidemiology, evolution, and pathogenesis of h7n9 influenza viruses in five epidemic waves since 2013 in China. Trends Microbiol. 2017;25(9):713–28.PubMedCrossRef

Zhu H, Lam TT, Smith DK, Guan Y. Emergence and development of H7N9 influenza viruses in China. Curr Opin Virol. 2016;16:106–13.PubMedCrossRef

Zhang Q, Shi J, Deng G, Guo J, Zeng X, He X, et al. H7N9 influenza viruses are transmissible in ferrets by respiratory droplet. Science. 2013;341(6144):410–4.PubMedCrossRef

Shi J, Deng G, Kong H, Gu C, Ma S, Yin X, et al. H7N9 virulent mutants detected in chickens in China pose an increased threat to humans. Cell Res. 2017;27(12):1409–21.PubMedPubMedCentralCrossRef

Yin X, Deng G, Zeng X, Cui P, Hou Y, Liu Y, et al. Genetic and biological properties of H7N9 avian influenza viruses detected after application of the H7N9 poultry vaccine in China. PLoS Pathog. 2021;17(4):e1009561.PubMedPubMedCentralCrossRef

Liang L, Jiang L, Li J, Zhao Q, Wang J, He X, et al. Low polymerase activity attributed to PA drives the acquisition of the PB2 E627K mutation of H7N9 avian influenza virus in mammals. MBio. 2019;10(3):e01162-e1219.PubMedPubMedCentralCrossRef

Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013;368(20):1888–97.PubMedCrossRef

Wan X, Li J, Wang Y, Yu X, He X, Shi J, et al. H7N9 virus infection triggers lethal cytokine storm by activating gasdermin E-mediated pyroptosis of lung alveolar epithelial cells. Natl Sci Rev. 2022;9(1):nwab137.PubMedCrossRef

10.

Carty M, Guy C, Bowie AG. Detection of viral infections by innate immunity. Biochem Pharmacol. 2021;183:114316.PubMedCrossRef

11.

Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17(1):1–14.PubMedCrossRef

12.

Rehwinkel J, Gack MU. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol. 2020;20(9):537–51.PubMedPubMedCentralCrossRef

13.

Thoresen D, Wang W, Galls D, Guo R, Xu L, Pyle AM. The molecular mechanism of RIG-I activation and signaling. Immunol Rev. 2021;304(1):154–68.PubMedPubMedCentralCrossRef

14.

McGill J, Heusel JW, Legge KL. Innate immune control and regulation of influenza virus infections. J Leukoc Biol. 2009;86(4):803–12.PubMedPubMedCentralCrossRef

15.

Zhang J, Qiu Q, Wang H, Chen C, Luo D. TRIM46 contributes to high glucose-induced ferroptosis and cell growth inhibition in human retinal capillary endothelial cells by facilitating GPX4 ubiquitination. Exp Cell Res. 2021;407(2):112800.PubMedCrossRef

16.

Tantai J, Pan X, Chen Y, Shen Y, Ji C. TRIM46 activates AKT/HK2 signaling by modifying PHLPP2 ubiquitylation to promote glycolysis and chemoresistance of lung cancer cells. Cell Death Dis. 2022;13(3):285.PubMedPubMedCentralCrossRef

17.

Ren XB, Zhao J, Liang XF, Guo XD, Jiang SB, Xiang YZ. Identification TRIM46 as a potential biomarker and therapeutic target for clear cell renal cell carcinoma through comprehensive bioinformatics analyses. Front Med (Lausanne). 2021;8:785331.CrossRef

18.

Hsu SF, Su WC, Jeng KS, Lai MM. A host susceptibility gene, DR1, facilitates influenza A virus replication by suppressing host innate immunity and enhancing viral RNA replication. J Virol. 2015;89(7):3671–82.PubMedPubMedCentralCrossRef

19.

Shin D, Lee J, Park JH, Min JY. Double plant homeodomain fingers 2 (DPF2) promotes the immune escape of influenza virus by suppressing beta interferon production. J Virol. 2017;91(12):e02260.PubMedPubMedCentralCrossRef

20.

Chen X, Liu S, Goraya MU, Maarouf M, Huang S, Chen JL. Host Immune Response to Influenza A Virus Infection. Front Immunol. 2018;9:320.PubMedPubMedCentralCrossRef

21.

Sun X, Feng W, Guo Y, Wang Q, Dong C, Zhang M, et al. MCPIP1 attenuates the innate immune response to influenza A virus by suppressing RIG-I expression in lung epithelial cells. J Med Virol. 2018;90(2):204–11.PubMedCrossRef

22.

Li M, Qi W, Chang Q, Chen R, Zhen D, Liao M, et al. Influenza A virus protein PA-X suppresses host Ankrd17-mediated immune responses. Microbiol Immunol. 2021;65(1):48–59.PubMedCrossRef

23.

Gao S, Song L, Li J, Zhang Z, Peng H, Jiang W, et al. Influenza A virus-encoded NS1 virulence factor protein inhibits innate immune response by targeting IKK. Cell Microbiol. 2012;14(12):1849–66.PubMedCrossRef

24.

Tseng YY, Kuan CY, Mibayashi M, Chen CJ, Palese P, Albrecht RA, et al. Interaction between NS1 and cellular MAVS contributes to NS1 mitochondria targeting. Viruses. 2021;13(10):1909.PubMedPubMedCentralCrossRef

25.

Mesev EV, LeDesma RA, Ploss A. Decoding type I and III interferon signalling during viral infection. Nat Microbiol. 2019;4(6):914–24.PubMedPubMedCentralCrossRef

26.

Weis S, Te Velthuis AJW. Influenza virus RNA synthesis and the innate immune response. Viruses. 2021;13(5):780.PubMedPubMedCentralCrossRef

27.

Liu B, Li NL, Shen Y, Bao X, Fabrizio T, Elbahesh H, et al. The C-terminal tail of TRIM56 dictates antiviral restriction of influenza A and B viruses by impeding viral RNA synthesis. J Virol. 2016;90(9):4369–82.PubMedPubMedCentralCrossRef

28.

Wu X, Wang J, Wang S, Wu F, Chen Z, Li C, et al. Inhibition of influenza A virus replication by TRIM14 via Its multifaceted protein-protein interaction with NP. Front Microbiol. 2019;10:344.PubMedPubMedCentralCrossRef

29.

Lee HR, Lee MK, Kim CW, Kim M. TRIM proteins and their roles in the influenza virus life cycle. Microorganisms. 2020;8(9):1424.PubMedCentralCrossRef

30.

Sun N, Jiang L, Ye M, Wang Y, Wang G, Wan X, et al. TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2. Protein Cell. 2020;11(12):894–914.PubMedPubMedCentralCrossRef

31.

Wang X, Xiong J, Zhou D, Zhang S, Wang L, Tian Q, et al. TRIM34 modulates influenza virus-activated programmed cell death by targeting Z-DNA-binding protein 1 for K63-linked polyubiquitination. J Biol Chem. 2022;298(3):101611.PubMedPubMedCentralCrossRef

32.

Xue B, Li H, Guo M, Wang J, Xu Y, Zou X, et al. TRIM21 promotes innate immune response to RNA viral infection through Lys27-linked polyubiquitination of MAVS. J Virol. 2018;92(14):e00321.PubMedPubMedCentralCrossRef

33.

Xing J, Zhang A, Minze LJ, Li XC, Zhang Z. TRIM29 negatively regulates the type I IFN production in response to RNA virus. J Immunol. 2018;201(1):183–92.PubMedCrossRef

34.

Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA. Pattern recognition receptors and the innate immune response to viral infection. Viruses. 2011;3(6):920–40.PubMedPubMedCentralCrossRef

35.

Kell AM, Gale M Jr. RIG-I in RNA virus recognition. Virology. 2015;479–480:110–21.PubMedCrossRef

36.

Fernandes-Santos C, Azeredo EL. Innate immune response to dengue virus: toll-like receptors and antiviral response. Viruses. 2022;14(5):992.PubMedPubMedCentralCrossRef

37.

Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441(7089):101–5.PubMedCrossRef

38.

Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol. 2014;14(5):315–28.PubMedPubMedCentralCrossRef

39.

Liu G, Zhou Y. Cytoplasm and beyond: dynamic innate immune sensing of influenza A virus by RIG-I. J Virol. 2019;93(8):e02299.PubMedPubMedCentralCrossRef

40.

Sui L, Zhao Y, Wang W, Wu P, Wang Z, Yu Y, et al. SARS-CoV-2 membrane protein inhibits type I interferon production through ubiquitin-mediated degradation of TBK1. Front Immunol. 2021;12:662989.PubMedPubMedCentralCrossRef

41.

Huang L, Liu H, Zhang K, Meng Q, Hu L, Zhang Y, et al. Ubiquitin-conjugating enzyme 2S enhances viral replication by inhibiting type I IFN production through recruiting USP15 to Deubiquitinate TBK1. Cell Rep. 2020;32(7):108044.PubMedCrossRef

42.

Zhan Z, Cao H, Xie X, Yang L, Zhang P, Chen Y, et al. Phosphatase PP4 negatively regulates type I IFN production and antiviral innate immunity by dephosphorylating and deactivating TBK1. J Immunol. 2015;195(8):3849–57.PubMedCrossRef

43.

Li D, Yang W, Ren J, Ru Y, Zhang K, Fu S, et al. The E3 Ubiquitin ligase TBK1 mediates the degradation of multiple picornavirus VP3 proteins by phosphorylation and ubiquitination. J Virol. 2019;93(23):e01438.PubMedPubMedCentralCrossRef

44.

Song G, Liu B, Li Z, Wu H, Wang P, Zhao K, et al. E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1. Nat Immunol. 2016;17(12):1342–51.PubMedCrossRef

45.

Huang L, Xu W, Liu H, Xue M, Liu X, Zhang K, et al. African swine fever virus pI215L negatively regulates cGAS-STING signaling pathway through recruiting RNF138 to inhibit K63-linked ubiquitination of TBK1. J Immunol. 2021;207(11):2754–69.PubMedCrossRef

Title: Tripartite motif-containing protein 46 accelerates influenza A H7N9 virus infection by promoting K48-linked ubiquitination of TBK1
Authors: Wei Su
Xian-Tian Lin
Shuai Zhao
Xiao-Qin Zheng
Yu-Qing Zhou
Lan-Lan Xiao
Hui Chen
Zheng-Yu Zhang
Li-Jun Zhang
Xiao-Xin Wu
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Influenza
Interferon
Published in: Virology Journal / Issue 1/2022
Electronic ISSN: 1743-422X
DOI: https://doi.org/10.1186/s12985-022-01907-x

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Tripartite motif-containing protein 46 accelerates influenza A H7N9 virus infection by promoting K48-linked ubiquitination of TBK1

Abstract

Background

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2022

Discovery of vaccine-like recombinant SARS-CoV-2 circulating in human

Disseminated cryptococcosis with varicella-zoster virus coinfection of idiopathic CD4 + T lymphocytopenia: a case report and literature review

SARS-CoV-2 infection in pediatric population before and during the Delta (B.1.617.2) and Omicron (B.1.1.529) variants era

Molecular characterization of enterovirus detected in cerebrospinal fluid and wastewater samples in Monastir, Tunisia, 2014–2017

Identification and application of a pair of noncompeting monoclonal antibodies broadly binding to the nucleocapsid proteins of SARS-CoV-2 variants including Omicron

SARS-CoV2 RT-PCR assays: In vitro﻿ comparison of 4 WHO approved protocols on clinical specimens and its implications for real laboratory practice through variant emergence

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

SARS-CoV2 RT-PCR assays: In vitro comparison of 4 WHO approved protocols on clinical specimens and its implications for real laboratory practice through variant emergence