TRAF7 Negatively Regulates the RLR Signaling Pathway by Facilitating the K48-linked Ubiquitination of TBK1

Overview

Journal Virol Sin

Specialty Microbiology

Date 2023 Apr 22

PMID 37086853

Authors

Jing-Ping Huang

Ya-Xian Yang

Tian Chen

Dan-Dan Wang

Jing Li

Liang-Guo Xu

Affiliations

Soon will be listed here.

Abstract

TANK-binding kinase 1 (TBK1) is a nodal protein involved in multiple signal transduction pathways. In RNA virus-mediated innate immunity, TBK1 is recruited to the prion-like platform formed by MAVS and subsequently activates the transcription factors IRF3/7 and NF-κB to produce type I interferon (IFN) and proinflammatory cytokines for the signaling cascade. In this study, TRAF7 was identified as a negative regulator of innate immune signaling. TRAF7 interacts with TBK1 and promotes K48-linked polyubiquitination and degradation of TBK1 through its RING domain, impairing the activation of IRF3 and the production of IFN-β. In addition, we found that the conserved cysteine residues at position 131 of TRAF7 are necessary for its function toward TBK1. Knockout of TRAF7 could facilitate the activation of IRF3 and increase the transcript levels of downstream antiviral genes. These data suggest that TRAF7 negatively regulates innate antiviral immunity by promoting the K48-linked ubiquitination of TBK1.

Citing Articles

The Inc Tri1 interacts with TRAF7 to displace native TRAF7 interacting partners.

Herrera C, McMahon E, Swaney D, Sherry J, Pha K, Adams-Boone K Microbiol Spectr. 2024; 12(7):e0045324.

PMID: 38814079 PMC: 11218536. DOI: 10.1128/spectrum.00453-24.

Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1.

Xiao Z, Dai C, Yu T, Zhu J, Pan Y, Shuai W Int J Biol Sci. 2024; 20(5):1815-1832.

PMID: 38481817 PMC: 10929191. DOI: 10.7150/ijbs.85562.

References

Barber G . Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses. Curr Opin Immunol. 2011; 23(1):10-20. PMC: 3881186. DOI: 10.1016/j.coi.2010.12.015. View

Wang Y, Wang F, Wu Y, Zuo L, Zhang S, Zhou Q . MicroRNA-126 attenuates palmitate-induced apoptosis by targeting TRAF7 in HUVECs. Mol Cell Biochem. 2014; 399(1-2):123-30. DOI: 10.1007/s11010-014-2239-4. View

Tan X, Sun L, Chen J, Chen Z . Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids. Annu Rev Microbiol. 2018; 72:447-478. DOI: 10.1146/annurev-micro-102215-095605. View

He T, Chen T, Wang D, Xu L . HAUS8 regulates RLR‑VISA antiviral signaling positively by targeting VISA. Mol Med Rep. 2018; 18(2):2458-2466. DOI: 10.3892/mmr.2018.9171. View

Ling T, Li S, Weng G, Wang W, Li C, Cao L . TARBP2 negatively regulates IFN-β production and innate antiviral response by targeting MAVS. Mol Immunol. 2018; 104:1-10. DOI: 10.1016/j.molimm.2018.10.017. View

Zhang Q, Zhang X, Dong W . TRAF7 contributes to tumor progression by promoting ubiquitin-proteasome mediated degradation of P53 in hepatocellular carcinoma. Cell Death Discov. 2021; 7(1):352. PMC: 8590685. DOI: 10.1038/s41420-021-00749-w. View

Ivashkiv L, Donlin L . Regulation of type I interferon responses. Nat Rev Immunol. 2013; 14(1):36-49. PMC: 4084561. DOI: 10.1038/nri3581. View

Zhu Z, Aref A, Cohoon T, Barbie T, Imamura Y, Yang S . Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov. 2014; 4(4):452-65. PMC: 3980023. DOI: 10.1158/2159-8290.CD-13-0646. View

Oral E, Reilly S, Gomez A, Meral R, Butz L, Ajluni N . Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes. Cell Metab. 2017; 26(1):157-170.e7. PMC: 5663294. DOI: 10.1016/j.cmet.2017.06.006. View

10.

Zotti T, Uva A, Ferravante A, Vessichelli M, Scudiero I, Ceccarelli M . TRAF7 protein promotes Lys-29-linked polyubiquitination of IkappaB kinase (IKKgamma)/NF-kappaB essential modulator (NEMO) and p65/RelA protein and represses NF-kappaB activation. J Biol Chem. 2011; 286(26):22924-33. PMC: 3123060. DOI: 10.1074/jbc.M110.215426. View

11.

Li X, Zhang Q, Ding Y, Liu Y, Zhao D, Zhao K . Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat Immunol. 2016; 17(7):806-15. DOI: 10.1038/ni.3464. View

12.

Morita Y, Kanei-Ishii C, Nomura T, Ishii S . TRAF7 sequesters c-Myb to the cytoplasm by stimulating its sumoylation. Mol Biol Cell. 2005; 16(11):5433-44. PMC: 1266438. DOI: 10.1091/mbc.e05-08-0731. View

13.

Lei C, Zhong B, Zhang Y, Zhang J, Wang S, Shu H . Glycogen synthase kinase 3β regulates IRF3 transcription factor-mediated antiviral response via activation of the kinase TBK1. Immunity. 2010; 33(6):878-89. DOI: 10.1016/j.immuni.2010.11.021. View

14.

Ma X, Helgason E, Phung Q, Quan C, Iyer R, Lee M . Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation. Proc Natl Acad Sci U S A. 2012; 109(24):9378-83. PMC: 3386122. DOI: 10.1073/pnas.1121552109. View

15.

Song G, Liu B, Li Z, Wu H, Wang P, Zhao K . E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1. Nat Immunol. 2016; 17(12):1342-1351. DOI: 10.1038/ni.3588. View

16.

Huang L, Liu H, Zhang K, Meng Q, Hu L, Zhang Y . 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. DOI: 10.1016/j.celrep.2020.108044. View

17.

Zhang M, Wang L, Zhao X, Zhao K, Meng H, Zhao W . TRAF-interacting protein (TRIP) negatively regulates IFN-β production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1. J Exp Med. 2012; 209(10):1703-11. PMC: 3457734. DOI: 10.1084/jem.20120024. View

18.

Xu L, Wang Y, Han K, Li L, Zhai Z, Shu H . VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005; 19(6):727-40. DOI: 10.1016/j.molcel.2005.08.014. View

19.

Kawai T, Akira S . Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci. 2008; 1143:1-20. DOI: 10.1196/annals.1443.020. View

20.

Bouwmeester T, Bauch A, Ruffner H, Angrand P, Bergamini G, Croughton K . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 2004; 6(2):97-105. DOI: 10.1038/ncb1086. View