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ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for
Hepatitis C Virus Production
#MMPMID27124600
Vieyres G
; Welsch K
; Gerold G
; Gentzsch J
; Kahl S
; Vondran FW
; Kaderali L
; Pietschmann T
PLoS Pathog
2016[Apr]; 12
(4
): e1005568
PMID27124600
show ga
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 (?/? 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.
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