Targeting the SREBP-Dependent Lipidomic Reprogramming by Virus Infection for Broad-Spectrum Therapeutic Intervention
1State Key Laboratory of Emerging Infectious Diseases, 2Department of Microbiology, 3Carol Yu Centre for Infection, 4The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
Viruses are obligate intracellular parasites that exploit the host metabolic machineries to meet their extraordinary biosynthetic demands. A key component in such reprogramming is the rapid upregulation of lipid biosynthetic pathways, which can substantially impact the outcome of infection. Integrative transcriptomic and lipidomic profiling confirmed that Middle East respiratory syndrome coronavirus (MERS-CoV) infection reprograms the host lipid metabolism. By exploring a bioactive lipid library, we identified a tool compound, AM580 which is highly potent in interrupting the life cycle of diverse viruses including MERS-CoV and influenza A virus. Using click chemistry, the sterol regulatory element binding protein (SREBP) was identified as the primary cellular target of AM580 which accounts for its broad-spectrum antiviral activity. Mechanistic studies pinpoint multiple SREBP proteolytic processes and SREBP-regulated lipid biosynthesis pathways, including the downstream viral protein palmitoylation and double-membrane vesicles formation, that are indispensable for virus replication. Specially, AM580 blocked the interaction of SREBP1/2 proteins with the non-palindromic sterol regulatory elements (SREs) in the promoter/enhancer regions of multiple lipogenic genes, which inhibited their transcription and thus reversed the virus-induced lipid hyper-biosynthesis. Our study identifies a basic lipogenic transactivation event with broad relevance to human viral infections and represents SREBP as an ideal target for the development of broad-spectrum intervention strategies, especially for tackling novel viruses causing emerging infectious diseases.
This work was partly supported by the donations of the Michael Seak-Kan Tong, Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, and the Hong Kong Hainan Commercial Association South China Microbiology Research Fund; and funding from the Theme-based Research Scheme (T11-707/15-R) of the Research Grants Council, Hong Kong Special Administrative Region.