Cargando…

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

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 do...

Descripción completa

Detalles Bibliográficos
Autores principales: Vieyres, Gabrielle, Welsch, Kathrin, Gerold, Gisa, Gentzsch, Juliane, Kahl, Sina, Vondran, Florian W. R., Kaderali, Lars, Pietschmann, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849665/
https://www.ncbi.nlm.nih.gov/pubmed/27124600
http://dx.doi.org/10.1371/journal.ppat.1005568
_version_ 1782429573689901056
author Vieyres, Gabrielle
Welsch, Kathrin
Gerold, Gisa
Gentzsch, Juliane
Kahl, Sina
Vondran, Florian W. R.
Kaderali, Lars
Pietschmann, Thomas
author_facet Vieyres, Gabrielle
Welsch, Kathrin
Gerold, Gisa
Gentzsch, Juliane
Kahl, Sina
Vondran, Florian W. R.
Kaderali, Lars
Pietschmann, Thomas
author_sort Vieyres, Gabrielle
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4849665
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-48496652016-05-07 ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production Vieyres, Gabrielle Welsch, Kathrin Gerold, Gisa Gentzsch, Juliane Kahl, Sina Vondran, Florian W. R. Kaderali, Lars Pietschmann, Thomas PLoS Pathog Research Article 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. Public Library of Science 2016-04-28 /pmc/articles/PMC4849665/ /pubmed/27124600 http://dx.doi.org/10.1371/journal.ppat.1005568 Text en © 2016 Vieyres et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Vieyres, Gabrielle
Welsch, Kathrin
Gerold, Gisa
Gentzsch, Juliane
Kahl, Sina
Vondran, Florian W. R.
Kaderali, Lars
Pietschmann, Thomas
ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production
title ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production
title_full ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production
title_fullStr ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production
title_full_unstemmed ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production
title_short ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production
title_sort abhd5/cgi-58, the chanarin-dorfman syndrome protein, mobilises lipid stores for hepatitis c virus production
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849665/
https://www.ncbi.nlm.nih.gov/pubmed/27124600
http://dx.doi.org/10.1371/journal.ppat.1005568
work_keys_str_mv AT vieyresgabrielle abhd5cgi58thechanarindorfmansyndromeproteinmobiliseslipidstoresforhepatitiscvirusproduction
AT welschkathrin abhd5cgi58thechanarindorfmansyndromeproteinmobiliseslipidstoresforhepatitiscvirusproduction
AT geroldgisa abhd5cgi58thechanarindorfmansyndromeproteinmobiliseslipidstoresforhepatitiscvirusproduction
AT gentzschjuliane abhd5cgi58thechanarindorfmansyndromeproteinmobiliseslipidstoresforhepatitiscvirusproduction
AT kahlsina abhd5cgi58thechanarindorfmansyndromeproteinmobiliseslipidstoresforhepatitiscvirusproduction
AT vondranflorianwr abhd5cgi58thechanarindorfmansyndromeproteinmobiliseslipidstoresforhepatitiscvirusproduction
AT kaderalilars abhd5cgi58thechanarindorfmansyndromeproteinmobiliseslipidstoresforhepatitiscvirusproduction
AT pietschmannthomas abhd5cgi58thechanarindorfmansyndromeproteinmobiliseslipidstoresforhepatitiscvirusproduction