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NAMPT Antagonizes Tegument Protein Incorporation to Restrict Herpesvirus Lytic Replication

83 Pages Posted: 20 Mar 2019 Publication Status: Review Complete

See all articles by Na Xie

Na Xie

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

Shu Zhang

University of Southern California - Section of Infection and Immunity

Mao Tian

University of Southern California - Section of Infection and Immunity

Jun Xiao

University of Southern California - Section of Infection and Immunity; Hunan Normal University - Key Laboratory of Protein Chemistry and Developmental Biology

Junjie Zhang

University of Southern California - Department of Molecular Microbiology and Immunology

Jun Zhao

University of Southern California - Department of Molecular Microbiology and Immunology

Jessica Carriere

University of Southern California - Section of Infection and Immunity

Junhua Li

University of Southern California - Department of Molecular Microbiology and Immunology; University of Southern California - Section of Infection and Immunity

Kui Wang

Sichuan University - State Key Laboratory of Biotherapy; Sichuan University - Cancer Center; Sichuan University - National Collaborative Innovation Center for Biotherapy

Hao Feng

Hunan Normal University - Key Laboratory of Protein Chemistry and Developmental Biology

Richard Longnecker

Northwestern University - Department of Microbiology-Immunology

Yuquan Wei

Sichuan University - State Key Laboratory of Biotherapy; Sichuan University - Cancer Center; Sichuan University - National Collaborative Innovation Center for Biotherapy

Canhua Huang

Sichuan University - National Collaborative Innovation Center for Biotherapy

Pinghui Feng

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

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Abstract

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)

Suggested Citation

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.

Na Xie

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

University of Southern California - Section of Infection and Immunity

925 W 34th Street
Los Angeles, CA 90089
United States

Sichuan University - State Key Laboratory of Biotherapy

Chengdu
China

Sichuan University - Cancer Center

Chengdu
China

Sichuan University - National Collaborative Innovation Center for Biotherapy

Chengdu, Sichuan 610041
China

Shu Zhang

University of Southern California - Section of Infection and Immunity

925 W 34th Street
Los Angeles, CA 90089
United States

Mao Tian

University of Southern California - Section of Infection and Immunity

925 W 34th Street
Los Angeles, CA 90089
United States

Jun Xiao

University of Southern California - Section of Infection and Immunity

925 W 34th Street
Los Angeles, CA 90089
United States

Hunan Normal University - Key Laboratory of Protein Chemistry and Developmental Biology

Changsha, Hunan 410081
China

Junjie Zhang

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

Jun Zhao

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

Jessica Carriere

University of Southern California - Section of Infection and Immunity

925 W 34th Street
Los Angeles, CA 90089
United States

Junhua Li

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

University of Southern California - Section of Infection and Immunity

925 W 34th Street
Los Angeles, CA 90089
United States

Kui Wang

Sichuan University - State Key Laboratory of Biotherapy

Chengdu
China

Sichuan University - Cancer Center

Chengdu
China

Sichuan University - National Collaborative Innovation Center for Biotherapy

Chengdu, Sichuan 610041
China

Hao Feng

Hunan Normal University - Key Laboratory of Protein Chemistry and Developmental Biology

Changsha, Hunan 410081
China

Richard Longnecker

Northwestern University - Department of Microbiology-Immunology

Chicago, IL 60611
United States

Yuquan Wei

Sichuan University - State Key Laboratory of Biotherapy

Chengdu
China

Sichuan University - Cancer Center

Chengdu
China

Sichuan University - National Collaborative Innovation Center for Biotherapy

Chengdu, Sichuan 610041
China

Canhua Huang

Sichuan University - National Collaborative Innovation Center for Biotherapy

Chengdu, Sichuan 610041
China

Pinghui Feng (Contact Author)

University of Southern California - Department of Molecular Microbiology and Immunology ( email )

1450 Biggy Street
Los Angeles, CA 90089
United States

University of Southern California - Section of Infection and Immunity ( email )

925 W 34th Street
Los Angeles, CA 90089
United States

Sichuan University - State Key Laboratory of Biotherapy ( email )

Chengdu
China

Sichuan University - Cancer Center ( email )

Chengdu
China

Sichuan University - National Collaborative Innovation Center for Biotherapy ( email )

Chengdu, Sichuan 610041
China

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