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TANK-binding kinase 1 (TBK1) is crucial in producing type Ⅰ interferons (IFN-Ⅰ) that play critical functions in antiviral innate immunity. The tight regulation of TBK1, especially its activation, is very important. Here we identify NLRC4 as a positive regulator of TBK1. Ectopic expression of NLRC4 facilitates the activation of the IFN-β promoter, the mRNA levels of IFN-β, ISG54, and ISG56, and the nuclear translocation of interferon regulatory factor 3 induced by cGAS and STING. Consistently, under herpes simplex virus-1 (HSV-1) infection, knockdown or knockout of NLRC4 in BJ cells and primary peritoneal macrophages from Nlrc4-deficient (Nlrc4 -/- ) mice show attenuated Ifn-β, Isg54, and Isg56 mRNA transcription, TBK1 phosphorylation, and augmented viral replications. Moreover, Nlrc4 -/- mice show higher mortality upon HSV-1 infection. Mechanistically, NLRC4 facilitates the interaction between TBK1 and the E3 ubiquitin ligase CBL to enhance the K63-linked polyubiquitination of TBK1. Our study elucidates a previously uncharacterized function for NLRC4 in upregulating the cGAS-STING signaling pathway and antiviral innate immunity.

Titel:	NLRC4 promotes the cGAS-STING signaling pathway by facilitating CBL-mediated K63-linked polyubiquitination of TBK1.
Autor/in / Beteiligte Person:	Zhang, R ; Yang, W ; Zhu, H ; Zhai, J ; Xue, M ; Zheng, C
Link:	Zum Volltext
Zeitschrift:	Journal of medical virology, Jg. 95 (2023-08-01), Heft 8, S. e29013
Veröffentlichung:	New York Ny : Wiley-Liss ; <i>Original Publication</i>: New York, Liss., 2023
Medientyp:	academicJournal
ISSN:	1096-9071 (electronic)
DOI:	10.1002/jmv.29013
Schlagwort:	Animals Mice Antiviral Agents metabolism Immunity, Innate Nucleotidyltransferases genetics Nucleotidyltransferases metabolism Phosphorylation Ubiquitination Herpes Simplex genetics Herpesvirus 1, Human genetics Signal Transduction genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [J Med Virol] 2023 Aug; Vol. 95 (8), pp. e29013. MeSH Terms: Herpes Simplex* / genetics ; Herpesvirus 1, Human* / genetics ; Signal Transduction* / genetics ; Animals ; Mice ; Antiviral Agents / metabolism ; Immunity, Innate ; Nucleotidyltransferases / genetics ; Nucleotidyltransferases / metabolism ; Phosphorylation ; Ubiquitination References: Ablasser A, Hur S. Regulation of cGAS- and RLR-mediated immunity to nucleic acids. Nat Immunol. 2020;21:17-29. ; Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet. 2019;20:657-674. ; Zhu H, Zheng C. When PARPs meet antiviral innate immunity. TIM. 2021;29:776-778. ; Su C, Zheng C. When Rab GTPases meet innate immune signaling pathways. Cytokine Growth Factor Rev. 2021;59:95-100. ; Cai C, Tang YD, Zhai J, Zheng C. 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Contributed Indexing: Keywords: CBL; HSV-1; NLRC4; TBK1; cGAS-STING signaling pathway Substance Nomenclature: 0 (Antiviral Agents) ; EC 2.7.7.- (Nucleotidyltransferases) ; 0 (Ipaf protein, mouse) ; EC 2.7.1.- (Tbk1 protein, mouse) ; 0 (Sting1 protein, mouse) ; EC 2.7.7.- (cGAS protein, mouse) Entry Date(s): Date Created: 20230804 Date Completed: 20230807 Latest Revision: 20230809 Update Code: 20231215

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NLRC4 promotes the cGAS-STING signaling pathway by facilitating CBL-mediated K63-linked polyubiquitination of TBK1.