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Species-specific Deamidation of cGAS Facilitates Herpes Simplex Virus Lytic Replication

69 Pages Posted: 9 Jun 2018 Publication Status: Published

See all articles by Junjie Zhang

Junjie Zhang

University of Southern California - Department of Molecular Microbiology and Immunology

Jun Zhao

University of Southern California - Department of Molecular Microbiology and Immunology

Junhua Li

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

Simin Xu

University of Southern California - Department of Molecular Microbiology and Immunology

Shanping He

University of Southern California - Department of Molecular Microbiology and Immunology; Hunan Normal University - College of Life Science

Yi Zeng

Youjiang Medical University for Nationalities

Linshen Xie

Sichuan University - West China Hospital

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

Ting Liu

University of Southern California - Department of Molecular Microbiology and Immunology

Katie Lee

University of Southern California - Department of Molecular Microbiology and Immunology

Gil Ju Seo

University of Southern California - Department of Molecular Microbiology and Immunology

Lin Chen

University of Southern California - Department of Biological Sciences; University of Southern California - Department of Chemistry

Alex C. Stabell

University of Colorado at Boulder - BioFrontiers Institute; University of Colorado at Boulder - Department of Molecular, Cell, and Developmental Biology

Zanxian Xia

Central South University - School of Life Sciences

Sarah L. Sawyer

University of Colorado at Boulder - BioFrontiers Institute; University of Colorado at Boulder - Department of Molecular, Cell, and Developmental Biology

Jae Jung

University of Southern California - Department of Molecular Microbiology and Immunology

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

Host innate immune pathways are highly conserved in higher eukaryotes. Significance of the species-specific variation of innate immune components has not been explored with regard to DNA viruses. Here, we report the identification of a single site variation that defines the resistance of the cytosolic DNA sensor cGAS of nonhuman primates (NHPs) to deamidation mediated by human herpes simplex virus 1 (HSV-1). HSV-1 UL37, but not the deamidase-deficient UL37C819S mutant, deamidated human and mouse cGAS in vitro and in transfected cells. Biochemical analysis identified four sites of deamidation distributed throughout the Mab21 domain of cGAS. While deamidation did not significantly impair the DNA-binding and self-dimerizing activities of cGAS, deamidated cGAS failed to catalyze the synthesis of cGAMP that activates innate immune signaling to restrict DNA virus replication. Moreover, recombinant HSV-1 carrying the deamidase-inactivating C819S point mutation more robustly induced antiviral cytokine production and was highly attenuated in replication and pathogenesis in mice compared to HSV-1 wild-type, in a cGAS- and STING-dependent manner. Sequence comparison and mutational analyses defined a single asparagine within the activation loop of cGAS of human and mouse, but not most NHP cGASs, which underpins cGAS deamidation by UL37 and species permissiveness of HSV-1. This work uncovers a key role of protein deamidation in immune evasion whereby a human pathogen has evolved to exploit species sequence variation to disarm host immune defense.

Suggested Citation

Zhang, Junjie and Zhao, Jun and Li, Junhua and Xu, Simin and He, Shanping and Zeng, Yi and Xie, Linshen and Xie, Na and Liu, Ting and Lee, Katie and Seo, Gil Ju and Chen, Lin and Stabell, Alex C. and Xia, Zanxian and Sawyer, Sarah L. and Jung, Jae and Huang, Canhua and Feng, Pinghui, Species-specific Deamidation of cGAS Facilitates Herpes Simplex Virus Lytic Replication (2018). Available at SSRN: https://ssrn.com/abstract=3188495 or http://dx.doi.org/10.2139/ssrn.3188495
This version of the paper has not been formally peer reviewed.

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

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

Simin Xu

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

Shanping He

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

Hunan Normal University - College of Life Science

No. 36, Lushan Road
Yuelu District
Changsha, Hunan 410001
China

Yi Zeng

Youjiang Medical University for Nationalities

Chengxiang Rd
Youjiang District
Baise, Guangxi
China

Linshen Xie

Sichuan University - West China Hospital

No 37, Guoxue Road
Wuhou District
Chengdu, Sichuan Province 610041
China

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

Ting Liu

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

Katie Lee

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

Gil Ju Seo

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

Lin Chen

University of Southern California - Department of Biological Sciences

3616 Trousdale Parkway, AHF 107
Los Angeles, CA 90089-0371
United States

University of Southern California - Department of Chemistry

Los Angeles, CA 90089-106
United States

Alex C. Stabell

University of Colorado at Boulder - BioFrontiers Institute

1070 Edinboro Drive
Boulder, CO 80309
United States

University of Colorado at Boulder - Department of Molecular, Cell, and Developmental Biology

1070 Edinboro Drive
Boulder, CO 80309
United States

Zanxian Xia

Central South University - School of Life Sciences

Changsha, Hunan 410008
China

Sarah L. Sawyer

University of Colorado at Boulder - BioFrontiers Institute

1070 Edinboro Drive
Boulder, CO 80309
United States

University of Colorado at Boulder - Department of Molecular, Cell, and Developmental Biology

1070 Edinboro Drive
Boulder, CO 80309
United States

Jae Jung

University of Southern California - Department of Molecular Microbiology and Immunology

1450 Biggy Street
Los Angeles, CA 90089
United States

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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