Research Article: ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production

Date Published: April 28, 2016

Publisher: Public Library of Science

Author(s): Gabrielle Vieyres, Kathrin Welsch, Gisa Gerold, Juliane Gentzsch, Sina Kahl, Florian W. R. Vondran, Lars Kaderali, Thomas Pietschmann, Timothy L. Tellinghuisen.

http://doi.org/10.1371/journal.ppat.1005568

Abstract

Hepatitis C virus (HCV) particles closely mimic human very-low-density lipoproteins (VLDL) to evade humoral immunity and to facilitate cell entry. However, the principles that govern HCV association with VLDL components are poorly defined. Using an siRNA screen, we identified ABHD5 (α/β hydrolase domain containing protein 5, also known as CGI-58) as a new host factor promoting both virus assembly and release. ABHD5 associated with lipid droplets and triggered their hydrolysis. Importantly, ABHD5 Chanarin-Dorfman syndrome mutants responsible for a rare lipid storage disorder in humans were mislocalised, and unable to consume lipid droplets or support HCV production. Additional ABHD5 mutagenesis revealed a novel tribasic motif that does not influence subcellular localization but determines both ABHD5 lipolytic and proviral properties. These results indicate that HCV taps into the lipid droplet triglyceride reservoir usurping ABHD5 lipase cofactor function. They also suggest that the resulting lipid flux, normally devoted to VLDL synthesis, also participates in the assembly and release of the HCV lipo-viro-particle. Altogether, our study provides the first association between the Chanarin-Dorfman syndrome protein and an infectious disease and sheds light on the hepatic manifestations of this rare genetic disorder as well as on HCV morphogenesis.

Partial Text

HCV chronically infects around 146 million people worldwide [1] and the associated cases of end-stage liver disease constitute a major indication for liver transplantation [2]. A hallmark of chronic hepatitis C is the dysregulation of the host lipid metabolism, notably with the occurrence of liver steatosis in 40% of chronically infected patients in absence of any other predisposition factor [3]. Curiously, the virion strikingly resembles very low density lipoproteins (VLDL) with its unusually low buoyant density, its association with apolipoproteins and peculiar lipid content [4–8]. This mimicry enables the use of lipid receptors in the virus entry process and facilitates the homing to liver cells as well as antibody escape [9]. It also suggested the involvement of the VLDL synthesis pathway in HCV morphogenesis. Indeed, in the course of virus assembly HCV modulates lipid droplets (LD), the principal cellular lipid storage organelles, by deposition of viral components and manipulation of LD motility [10,11]. This process is probably initiated by the viral core protein, which uses DGAT1 to translocate from the ER membrane onto the lipid droplet (LD) surface [12]. Assembly complexes are then built in the vicinity of the replication complexes and straddle ER membrane and lipid droplets [10]. Importantly, the VLDL-associated apolipoprotein ApoE is a critical factor for HCV assembly, while other liver-specific components of the VLDL machinery might be involved but can be bypassed [13,14]. However, the mechanisms that mediate the loading of HCV particles with apolipoproteins and VLDL lipids are poorly understood.

HCV usurps the host lipid metabolism at several steps of its replication cycle. Our rationale siRNA screen highlights and extends these intricate connections: out of the 19 gene candidates, 5 were specifically involved in HCV entry or replication, 7 in assembly or release and 3 in both early and late virus replication steps (Fig 1). To our knowledge, 9 of these factors have never been associated with HCV pro- or antiviral effects in cell culture (ABHD5, CES3, FABP1, PCYT1A, PLA2G6, PLD1, PSCM3, SEC22B and YWHAE). Interestingly, the 3 hits specifically involved in HCV assembly and release (PLA2G6, ABHD5 and FABP1) gathered in the glycerolipid metabolism cluster in a bioinformatic analysis or, in the case of ABHD5 and FABP1, have been reported to interact [42] (S1 Fig). Of note, FABP1 is involved in the life cycle of Plasmodium falciparum [43], a parasite sharing several other host factors with HCV (e.g. CD81 and SR-BI). Moreover, PLA2G6 is a phospholipase related to PLA2G4, which we previously reported as crucial for HCV assembly [44]. CHKA and PCYT1A were additional hits belonging to the same functional cluster and both take part in the synthesis pathway for phosphatidylcholine, a crucial constituent of membranes and VLDL particles [45]. This suggests that these factors might act cooperatively in a shared cellular and proviral function and that other HCV assembly cofactors might be found by further exploring this pathway. Collectively, these observations highlight the pivotal role of lipid remodelling processes for production of infectious HCV particles.

 

Source:

http://doi.org/10.1371/journal.ppat.1005568

 

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