Lipidomics identifi es a requirement for peroxisomal function during infl uenza virus replication

Journal of Lipid Research Volume 55, 2014 1357 Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc. for virus production. Host cell lipid metabolism and plasma membrane microdomains are implicated in the biogenesis of virus envelopes. Several studies have dissected the lipid inventory of purifi ed infl uenza virions ( 9, 10 ), whereas others have demonstrated the requirements for de novo fatty acid and sphingolipid biosynthesis and unique cholesterol compositions for virus production at budding sites ( 11–14 ). In addition to the importance of host cell lipid metabolism for the biogenesis of infl uenza virus envelopes, recent fi ndings suggest a major role for soluble lipid mediators in antiviral responses against infl uenza virus infection in vivo ( 15, 16 ). These soluble lipid mediators originate from membrane glycerophospholipids (GPLs) via phospholipase activity, and (to some extent), are metabolized in peroxisomes. For example, -oxidation in the peroxisome is crucial for the retroconversion of DHA, the precursor of the lipid mediator protectin D1, which prevents nuclear export of infl uenza virus RNAs; protectin D1 production is directly inhibited by infl uenza virus ( 15 ). The role of peroxisomes during infl uenza virus replication is further evident by interaction between infl uenza virus nonstructural protein 1 (NS1) and multifunctional protein 2 (MFP2/HSD17B4), an antiviral protein essential for peroxisomal -oxidation ( 17 ). Therefore, the collective literature indicates an apparent role for peroxisomes as the initial sites of antiviral signaling ( 18 ). Abstract Infl uenza virus acquires a host-derived lipid envelope during budding, yet a convergent view on the role of host lipid metabolism during infection is lacking. Using a mass spectrometry-based lipidomics approach, we provide a systems-scale perspective on membrane lipid dynamics of infected human lung epithelial cells and purifi ed infl uenza virions. We reveal enrichment of the minor peroxisomederived ether-linked phosphatidylcholines relative to bulk ester-linked phosphatidylcholines in virions as a unique pathogenicity-dependent signature for infl uenza not found in other enveloped viruses. Strikingly, pharmacological and genetic interference with peroxisomal and ether lipid metabolism impaired infl uenza virus production. Further integration of our lipidomics results with published genomics and proteomics data corroborated altered peroxisomal lipid metabolism as a hallmark of infl uenza virus infection in vitro and in vivo. Infl uenza virus may therefore tailor peroxisomal and particularly ether lipid metabolism for effi cient replication. —Tanner, L. B., C. Chng, X. L. Guan, Z. Lei, S. G. Rozen, and M. R. Wenk. Lipidomics identifi es a requirement for peroxisomal function during infl uenza virus replication. J. Lipid Res . 2014 . 55: 1357–1365 .

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