HSV-1 UL42 and UL47 hijack cellular nucleotide synthetic enzyme CAD to promote lytic replication
- 1Section of Infection and Immunity, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
- 2Department of Microbial Sciences in Health, Global Center for Pathogen Infection, Center for Experimental Therapeutics, Cleveland Clinic Research, Cleveland, Ohio, USA
Abstract
Cellular metabolic enzymes are well defined for their roles in metabolism, and their function beyond metabolism is poorly defined. Here, we report that herpes simplex virus 1 (HSV-1) couples evasion of the inflammatory response to metabolic activation to promote lytic replication. Specifically, HSV-1 activates carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD), which catalyzes the rate-limiting steps of de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. RelA deamidation suppresses NF-κB activation and the inflammatory response while simultaneously upregulating key glycolytic enzymes to promote aerobic glycolysis. Further affinity purification and functional assays identified HSV-1 UL42 and UL47 that interact with and activate CAD, recapitulating the phenotypes of RelA deamidation. Collectively, our work uncovers a role for a metabolic enzyme in coupling immune evasion to metabolic activation through its protein deamidase activity during HSV-1 infection, highlighting a potential therapeutic target.
IMPORTANCE: Host immune defense and cellular metabolism are two fundamental processes that shape viral pathogenesis. Here, we revealed that herpes simplex virus 1 (HSV-1) activates a nucleotide synthetic enzyme not only to support nucleotide synthesis but also to exploit its unconventional activity for immune evasion and metabolic reprogramming, highlighting a potential therapeutic target.
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BibTeX
@article{qin2026hsv1,
title = {{HSV-1 UL42 and UL47 hijack cellular nucleotide synthetic enzyme CAD to promote lytic replication}},
author = {Chao Qin and Xinchi Xie and Taolin Xie and Zhenhao An and Woo-Chang Chung and Pinghui Feng},
journal = {Journal of Virology},
year = {2026},
month = sep,
doi = {10.1128/jvi.00920-26},
url = {https://doi.org/10.1128/jvi.00920-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HSV-1 UL42 and UL47 hijack cellular nucleotide synthetic enzyme CAD to promote lytic replication
AU - Chao Qin
AU - Xinchi Xie
AU - Taolin Xie
AU - Zhenhao An
AU - Woo-Chang Chung
AU - Pinghui Feng
PY - 2026
DA - 2026/09/24
JO - Journal of Virology
DO - 10.1128/jvi.00920-26
UR - https://doi.org/10.1128/jvi.00920-26
AB - Cellular metabolic enzymes are well defined for their roles in metabolism, and their function beyond metabolism is poorly defined. Here, we report that herpes simplex virus 1 (HSV-1) couples evasion of the inflammatory response to metabolic activation to promote lytic replication. Specifically, HSV-1 activates carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD), which catalyzes the rate-limiting steps of de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. RelA deamidation suppresses NF-κB activation and the inflammatory response while simultaneously upregulating key glycolytic enzymes to promote aerobic glycolysis. Further affinity purification and functional assays identified HSV-1 UL42 and UL47 that interact with and activate CAD, recapitulating the phenotypes of RelA deamidation. Collectively, our work uncovers a role for a metabolic enzyme in coupling immune evasion to metabolic activation through its protein deamidase activity during HSV-1 infection, highlighting a potential therapeutic target. IMPORTANCE: Host immune defense and cellular metabolism are two fundamental processes that shape viral pathogenesis. Here, we revealed that herpes simplex virus 1 (HSV-1) activates a nucleotide synthetic enzyme not only to support nucleotide synthesis but also to exploit its unconventional activity for immune evasion and metabolic reprogramming, highlighting a potential therapeutic target.
SN - 0022-538X
SN - 1098-5514
ER -