Theranostics 2021; 11(15):7235-7246. doi:10.7150/thno.52934 This issue Cite

Research Paper

Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses

Xingying He1#, Tianliang Li2#, Kewei Qin3#, Shiyuan Luo4#, Zhenjie Li1#, Qingqing Ji1, Honghao Song1, Huyang He1, Hao Tang5✉, Chaofeng Han6✉, Hongjiao Li7✉, Yan Luo4✉

1. Department of Anesthesiology, Changzheng Hospital, Naval Medical University, Shanghai, China.
2. National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, China.
3. Central Laboratory and College of Otolaryngology Head and Neck Surgery, the Sixth Medical Center of Chinese PLA General Hospital, Beijing, China
4. Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
5. Department of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, China.
6. Department of Histoembryology and Shanghai Key Laboratory of Cell Engineering, Naval Medical University, Shanghai, China.
7. Department of Stomatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
# These authors contributed equally to this work.

Citation:
He X, Li T, Qin K, Luo S, Li Z, Ji Q, Song H, He H, Tang H, Han C, Li H, Luo Y. Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses. Theranostics 2021; 11(15):7235-7246. doi:10.7150/thno.52934. https://www.thno.org/v11p7235.htm
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Abstract

Graphic abstract

Rationale: Hosts defend against viral infection by sensing viral pathogen-associated molecular patterns and activating antiviral innate immunity through TBK1-IRF3 signaling. However, the underlying molecular mechanism remains unclear.

Methods: SiRNAs targeting Sirt1-7 were transfected into macrophages to screen the antiviral function. Sirt5 deficient mice or macrophages were subjected to viral infection to assess in vivo and in vitro function of Sirt5 by detecting cytokines, viral replicates and survival rate. Immunoprecipitation, WesternBlot and luciferase reporter assay were used to reveal molecular mechanism.

Results: In this study, we functionally screened seven Sirtuin family members, and found that Sirtuin5 (Sirt5) promotes antiviral signaling and responses. Sirt5 deficiency leads to attenuated antiviral innate immunity in vivo and in vitro upon viral infection by decreasing TBK1-IRF3 activation and type I IFN production. Sirt5 overexpression increased antiviral innate immunity. Mechanism investigation revealed that Sirt5 interacts with DDX3 and demalonylates DDX3, which is critical for TBK1-IRF3 activation. Mutation of the demalonylation lysine sites (K66, K130, and K162) of DDX3 increased ifnβ transcription. Furthermore, the acetylation on lysine 118 of DDX3 positively regulated ifnβ transcription, whereas Sirt5 could not deacetylate this site.

Conclusion: Sirt5 promotes anti- RNA and DNA virus innate immune responses by increasing TBK1 signaling through demalonylating DDX3, which identifies a novel regulatory pathway of antiviral innate immune response.

Keywords: Sirtuin, DDX3, TBK1, IRF3, IFN, viral infection


Citation styles

APA
He, X., Li, T., Qin, K., Luo, S., Li, Z., Ji, Q., Song, H., He, H., Tang, H., Han, C., Li, H., Luo, Y. (2021). Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses. Theranostics, 11(15), 7235-7246. https://doi.org/10.7150/thno.52934.

ACS
He, X.; Li, T.; Qin, K.; Luo, S.; Li, Z.; Ji, Q.; Song, H.; He, H.; Tang, H.; Han, C.; Li, H.; Luo, Y. Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses. Theranostics 2021, 11 (15), 7235-7246. DOI: 10.7150/thno.52934.

NLM
He X, Li T, Qin K, Luo S, Li Z, Ji Q, Song H, He H, Tang H, Han C, Li H, Luo Y. Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses. Theranostics 2021; 11(15):7235-7246. doi:10.7150/thno.52934. https://www.thno.org/v11p7235.htm

CSE
He X, Li T, Qin K, Luo S, Li Z, Ji Q, Song H, He H, Tang H, Han C, Li H, Luo Y. 2021. Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses. Theranostics. 11(15):7235-7246.

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