Abstract
Lipid droplets are essential cellular organelles for storage of fatty acids and triglycerides. The hepatitis C virus (HCV) translocates several of its proteins onto their surface and uses them for production of infectious progeny. We recently reported that the lipid droplet-associated α/β hydrolase domain-containing protein 5 (ABHD5/CGI-58) participates in HCV assembly by mobilizing lipid droplet-associated lipids. However, ABHD5 itself has no lipase activity and it remained unclear how ABHD5 mediates lipolysis critical for HCV assembly. Here, we identify adipose triglyceride lipase (ATGL) as ABHD5 effector and new host factor involved in the hepatic lipid droplet degradation as well as in HCV and lipoprotein morphogenesis. Modulation of ATGL protein expression and lipase activity controlled lipid droplet lipolysis and virus production. ABHD4 is a paralog of ABHD5 unable to activate ATGL or support HCV assembly and lipid droplet lipolysis. Grafting ABHD5 residues critical for activation of ATGL onto ABHD4 restored the interaction between lipase and co-lipase and bestowed the pro-viral and lipolytic functions onto the engineered protein. Congruently, mutation of the predicted ABHD5 protein interface to ATGL ablated ABHD5 functions in lipid droplet lipolysis and HCV assembly. Interestingly, minor alleles of ABHD5 and ATGL associated with neutral lipid storage diseases in human, are also impaired in lipid droplet lipolysis and their pro-viral functions. Collectively, these results show that ABHD5 cooperates with ATGL to mobilize triglycerides for HCV infectious virus production. Moreover, viral manipulation of lipid droplet homeostasis via the ABHD5-ATGL axis, akin to natural genetic variation in these proteins, emerges as a possible mechanism by which chronic HCV infection causes liver steatosis.
Highlights
Lipid droplets are the main intracellular neutral lipid storage reservoir and energy source [1]
Given that ABHD5 and to some extent adipose triglyceride lipase (ATGL) participate in lipoprotein secretion, our results indicate that lipid droplets might serve as a source for the lipids of the atypical hepatitis C virus (HCV) lipo-viro-particle
Mutation of the tribasic lipid droplet consumption motif (TBLC), KRK233-235, abrogated ABHD5 pro-lipolytic and pro-viral functions, without affecting the protein association with the lipid droplets [30]. This correlation between pro-lipolytic and pro-viral functions of ABHD5 suggested that ABHD5 participates in HCV morphogenesis by recruiting the triglycerides from the lipid droplets and that it exerts its role via the activation of a lipase
Summary
Lipid droplets are the main intracellular neutral lipid storage reservoir and energy source [1] They are dynamic organelles and capable of regulating the mobilization of the lipid stores depending on lipid availability and energy needs in the organism. One fourth of the global population has non-alcoholic fatty liver disease (NAFLD) and, is pre-disposed to develop liver cirrhosis or hepatocellular carcinoma. This prevalence is still rising, mostly due to the obesity epidemic [3]. Despite the commercialization of efficient antivirals, hepatitis C virus (HCV) still chronically infects 71 million people worldwide [5]. Several aspects of how these lipoviro-particles are built in the infected cells remain unclear
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