University of Southern California - Department of Molecular Microbiology and Immunology; University of Southern California - Section of Infection and Immunity; Sichuan University - State Key Laboratory of Biotherapy; Sichuan University - Cancer Center; Sichuan University - National Collaborative Innovation Center for Biotherapy
University of Southern California - Section of Infection and Immunity; Hunan Normal University - Key Laboratory of Protein Chemistry and Developmental Biology
University of Southern California - Department of Molecular Microbiology and Immunology; University of Southern California - Section of Infection and Immunity
Sichuan University - State Key Laboratory of Biotherapy; Sichuan University - Cancer Center; Sichuan University - National Collaborative Innovation Center for Biotherapy
Sichuan University - State Key Laboratory of Biotherapy; Sichuan University - Cancer Center; Sichuan University - National Collaborative Innovation Center for Biotherapy
University of Southern California - Department of Molecular Microbiology and Immunology; University of Southern California - Section of Infection and Immunity; Sichuan University - State Key Laboratory of Biotherapy; Sichuan University - Cancer Center; Sichuan University - National Collaborative Innovation Center for Biotherapy
Metabolic enzymes fuel the synthesis of macromolecules that underpin the proliferation of cells and propagation of pathogens. NAD is a key cofactor for enzymes catalyzing metabolic reactions. We report that NAMPT, the rate-limiting enzyme of the salvage pathway of NAD synthesis, antagonizes tegument protein incorporation and restricts herpesvirus lytic replication in an enzyme-independent manner. We demonstrated that NAMPT was packaged into the virion and reduced lytic replication of human herpes simplex virus 1 (HSV-1). Mechanistically, NAMPT targets two core tegument proteins, UL36 and UL37 that mesh a scaffold for viral tegumentation during lytic replication. As such, NAMPT competitively antagonizes the incorporation of diverse tegument proteins into the virion, impairing viral tegumentation and infectivity of the progeny. Microscopy analysis indicates that NAMPT localizes to the TGN, which HSV-1 capsids bud into during tegumentation. Finally, NAMPT exhibited antiviral activity against multiple herpesviruses and loss of NAMPT rendered mice highly susceptible to HSV-1 infection. This study defines a new restriction factor targeting herpesvirus tegumentation, revealing a metabolism-independent antiviral activity of a metabolic enzyme.
Keywords: Herpesviruses, tegument protein incorporation, restriction factor, intrinsic antiviral defense, the salvage NAD synthesis pathway, nicotinamide phosphoribosyl transferase (NAMPT)
Xie, Na and Zhang, Shu and Tian, Mao and Xiao, Jun and Zhang, Junjie and Zhao, Jun and Carriere, Jessica and Li, Junhua and Wang, Kui and Feng, Hao and Longnecker, Richard and Wei, Yuquan and Huang, Canhua and Feng, Pinghui, NAMPT Antagonizes Tegument Protein Incorporation to Restrict Herpesvirus Lytic Replication (March 19, 2019). Available at SSRN: https://ssrn.com/abstract=3354889 or http://dx.doi.org/10.2139/ssrn.3354889
This version of the paper has not been formally peer reviewed.
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