Alphaherpesvirus manipulates retinoic acid metabolism for optimal replication
Shengli Ming,
Shijun Zhang,
Jiayou Xing,
Guoyu Yang,
Lei Zeng,
Jiang Wang,
Beibei Chu
Affiliations
Shengli Ming
College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China; Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
Shijun Zhang
College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China; Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
Jiayou Xing
College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China; Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
Guoyu Yang
Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China; Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
Lei Zeng
College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China; Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; Corresponding author
Jiang Wang
College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China; Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou 450046, Henan Province, China; Corresponding author
Beibei Chu
College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China; Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou 450046, Henan Province, China; Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou 450046, Henan Province, China; Corresponding author
Summary: Retinoic acid (RA), derived from retinol (ROL), is integral to cell growth, differentiation, and organogenesis. It is known that RA can inhibit herpes simplex virus (HSV) replication, but the interactions between alphaherpesviruses and RA metabolism are unclear. Our present study revealed that alphaherpesvirus (HSV-1 and Pseudorabies virus, PRV) infections suppressed RA synthesis from ROL by activating P53, which increased retinol reductase 3 (DHRS3) expression—an enzyme that converts retinaldehyde back to ROL. This process depended on the virus-triggered DNA damage response, the degradation of class I histone deacetylases, and the subsequent hyperacetylation of histones H3 and H4. Counteracting DHRS3 or P53 enabled higher RA synthesis and reduced viral growth. RA enhanced antiviral defenses by promoting ABCA1- and ABCG1-mediated lipid efflux. Treatment with the retinoic acid receptor (RAR) agonist palovarotene protected mice from HSV-1 infection, thus providing a potential therapeutic strategy against viral infections.
