ARRDC4-mediated glycolysis enhances innate immunity to influenza A virus through fructose-1,6-bisphosphate
Abstract
Glucose metabolism impacts the innate immune response against viral infection. However, the key enzymes or the natural products and mechanisms involved are not well elucidated. Here, we found that arrestin domain containing 4 (ARRDC4), a critical regulator of glucose metabolism, senses influenza A virus (IAV) infection by interacting with viral PA protein. Upregulated ARRDC4 increases the enzymatic activity of phosphofructokinase, muscle type (PFKM) via binding its His298 site to promote the production of the metabolite fructose-1,6-bisphosphate (FBP). Consequently, FBP inhibits the K48-linked ubiquitination degradation of HSP90β, subsequently enhances its interaction with IKKβ and IKKε, and enhances NF-κB- and IRF7-mediated antiviral innate immunity, respectively. Importantly, FBP supplementation enhanced IFN-β-mediated antiviral innate immunity in vitro and in vivo. Our findings highlight a unique immunometabolic regulatory mechanism in which ARRDC4 senses IAV infection and regulates antiviral innate immunity through the PFKM-FBP metabolic axis and provide a strategy for manipulating FBP-related metabolism to treat viral infection.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Yuhan Li
Zhen Wang
Jie Wang
State Key Laboratory of Molecular Oncology, Beijing Key Laboratory, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology Cancer Hospital, Chinese Academy of Medical Sciences Beijing China
Zhimin Jiang
Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy
Mingyue Chen
State Key Laboratory of Veterinary Public Health and Safety, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, China Agricultural University
Hui Ai
State Key Laboratory of Veterinary Public Health and Safety, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, China Agricultural University
Chao Ma
Qi Tong
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Litao Liu
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Tony Velkov
Department of Pharmacology, Biodiscovery Institute, Monash University
Honglei Sun
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Juan Pu
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Jinhua Liu
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Chongshan Dai
State Key Laboratory of Veterinary Public Health and Safety, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, China Agricultural University
Yipeng Sun