Lipid metabolic pathways targeted during Zika virus infection
Yun Lan1, Joao Palma Pombo1, Jingshu Zhang1, Elizabeth Klemm4, Christoph Thiele3, Joseph Ashour2, and Sumana Sanyal1*
1HKU-Pasteur Research Pole, School of Public Health, School of Biomedical Sciences, LKS Faculty of Medicine, University of Hong Kong, Hong Kong; 2Mount Sinai School of Medicine, New York City, NY 10021, USA; 3Life and Medical Sciences Institute (LIMES), University of Bonn, Germany; 4Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
Post-translational modifications (PTMs) are central to spatial and temporal regulation of protein function. Ubiquitylation is one of the most versatile modifications, and frequently altered during virus infections. We employed a functional proteomics screen to target candidates that are differentially modified by ubiquitin upon flavivirus infections. Several lipid droplet associated proteins were isolated; amongst others, Aup1, a type-III membrane protein that is typically monoubiquitylated, was retrieved specifically in the unmodified form upon infection. Aup1 associated with viral NS4A and relocalized from lipid droplets to autophagosomes in virus-infected cells (Zhang et al., 2018). Production of flaviviruses, including dengue and Zika, was abolished in cells with Aup1 deletion or containing a mutant acyltransferase domain. Ubiquitylation disrupted the Aup1-NS4A interaction, resulting in inhibited acyltransferase activity, defective lipophagy and attenuated virus production. This phenomenon was coupled to redistribution of fatty acid synthase (FASN) to sites of viral replication. Gene depletion or pharmacological inhibition of FASN resulted in a significant reduction of virus replication. Our results indicate that alterations in lipid metabolic pathways including upregulation of fatty acid synthesis and lipophagy are mediated by viral nonstructural components NS3 and NS4A to facilitate replication and assembly of progeny virions. This mechanism appears to be a general phenomenon in biogenesis of flaviviruses and underscores the critical role of lipid metabolic pathways in virus infections.
Zhang, J., Lan, Y., Li, M.Y., Lamers, M.M., Fusade-Boyer, M., Klemm, E., Thiele, C., Ashour, J., and Sanyal, S. (2018). Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy and Drive Virus Production. Cell Host & Microbe 23, 819-831.e5.