HCV dispatches two of its viral proteins, core and NS5A, onto the surface of intracellular lipid droplets (LDs). We are interested in the mechanisms of how these viral proteins gain access to the LD surface and why association with LDs is a prerequisite for successful viral assembly. Contributions from the lab include demonstrations that LD association with both viral proteins is not random but requires the activity of one of the two triglyceride-synthesizing enzymes, DGAT1. We also showed that association of core with LDs is linked to a decrease of lipolysis of these droplets, de facto shielding the triglyceride stored in core-coated droplets from hydrolysis by the ATGL lipase and inducing steatosis in core-expressing mice or human cell lines. Another line of investigation identified the LD-associated protein TIP47 as a new interaction partner for NS5A, linking viral RNA replication directly with LDs. Current and future studies are centered on the question of why LDs are accessed and play a central role in the life cycle of certain viruses and how can this dependence be exploited for therapeutic strategies.
Camus G, Schweiger M, Herker E, Harris C, Kondratowicz AS, Tsou C-L, Farese RV, Herath K, Previs SF, Roddy TP, Pinto S, Zechner R, Ott M (2014) The hepatitis C virus core protein inhibits adipose triglyceride lipase (ATGL)-mediated lipid mobilization and enhances the ATGL interaction with comparative gene identification 58 (CGI-58) and lipid droplets. J Biol Chem
Camus G, Herker E, Modi AA, Haas JT, Ramage HR, Farese RV, Ott M (2013) Diacylglycerol acyltransferase-1 localizes hepatitis C virus NS5A protein to lipid droplets and enhances NS5A interaction with the viral capsid core. J Biol Chem 288:9915–9923.
Vogt DA, Camus G, Herker E, Webster BR, Tsou C-L, Greene WC, Yen T-SB, Ott M (2013) Lipid droplet-binding protein TIP47 regulates hepatitis C Virus RNA replication through interaction with the viral NS5A protein. PLoS Pathog 9:e1003302.
Herker E, Ott M (2012) Emerging role of lipid droplets in host/pathogen interactions. J Biol Chem 287:2280–2287.
Schröder S, Cho S, Zeng L, Zhang Q, Kaehlcke K, Mak L, Lau J, Bisgrove D, Schnolzer M, Verdin E, Zhou M-M, Ott M (2012) Two-pronged binding with bromodomain-containing protein 4 liberates positive transcription elongation factor b from inactive ribonucleoprotein complexes. J Biol Chem 287:1090–1099.
Harris C, Herker E, Farese RV, Ott M (2011) Hepatitis C virus core protein decreases lipid droplet turnover: a mechanism for core-induced steatosis. J Biol Chem 286:42615–42625.
Herker E, Ott M (2011) Unique ties between hepatitis C virus replication and intracellular lipids. Trends Endocrinol Metab 22:241–248.
Herker E, Harris C, Hernandez C, Carpentier A, Kaehlcke K, Rosenberg AR, Farese RV, Ott M (2010) Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med 16:1295–1298.