Influenza A virus infection activates STAT3 to enhance SREBP2 expression, cholesterol biosynthesis, and virus replication
Jingting Zhang,
Yunhan Wu,
Yujie Wang,
Penggang Liu,
Kaituo Liu,
Jing Sun,
Pinghu Zhang,
Xiaoquan Wang,
Xiufan Liu,
Xiulong Xu
Affiliations
Jingting Zhang
College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
Yunhan Wu
College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
Yujie Wang
College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
Penggang Liu
College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
Kaituo Liu
Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou 225009, Jiangsu Province, China
Jing Sun
College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
Pinghu Zhang
College of Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
Xiaoquan Wang
College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China; Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
Xiufan Liu
College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China; Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
Xiulong Xu
College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, China; Corresponding author
Summary: Cellular cholesterol plays an important role in influenza A virus (IAV) endocytosis and replication. However, how IAV infection regulates cholesterol biosynthesis remains poorly understood. Here, we report that IAV infection activates SREBP2 and induces the expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis pathway. SREBP2 deficiency suppresses IAV-induced HMGCR expression and virus replication. Mechanistically, IAV infection activates JAK2 and STAT3, inhibition of JAK2 and STAT3 activity by their inhibitors or by gene knockout downregulates IAV-induced SREBP2 and HMGCR expression and IAV replication, reduces the content of cellular cholesterol and virus binding to host cells. Exogenous cholesterol reverses the inhibitory effect of S3I-201 and STAT3 deficiency on virus replication. STAT3 or JAK2 overexpression increases the expression of SREBP2 and its downstream target genes, leading to increased IAV replication. These observations collectively suggest that STAT3 activation facilitates IAV replication by inducing SREBP2 expression and increasing cholesterol biosynthesis.
