ABHD5/ CGI-58 gene expression has been newly identified as central to hepatitis C viral assembly and release through the mobilization of lipid droplets, and mutated ABHD5/ CGI-58 not only causes the rare Chanarin-Dorfman Syndrome (CDS), but also interferes with HCV’s propagation and release efficiency, according to a study published in PLoS Pathogens.

According to the study researchers, this is the first study to connect CDS and an infectious disease and explain how the genetic disorder affects the liver. It also illuminates the morphogenesis of hepatitis C virus (HCV).

Gabrielle Vieyres, of the Institute of Experimental Virology at TWINCORE in the Centre for Experimental and Clinical Infection Research at the Medical School Hannover and the Helmholtz Centre for Infection Research in Hannover, Germany and colleagues tested 19 gene candidates using an siRNA screen that pointed to ABHD5/CGI-58 as one of the best genes responsible for forming and moving lipid droplets. 

“ABHD5 associated with lipid droplets and triggered their hydrolysis,” the researchers wrote in the study.


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HCV takes over these lipid droplets for reproduction in the host by mimicking very-low-density lipoproteins (VLDL) to enter cells, and this mechanism makes it difficult for the body’s immune system to locate and clear the pathogen.

Researchers noted that when ABHD5/CGI-58 is mutated, it causes Chanarin-Dorfman Syndrome, a lipid storage disorder that affects a person’s fat metabolism. ABHD5 Chanarin-Dorfman syndrome mutants were reported by investigators as mislocalized, and couldn’t “consume lipid droplets or support HCV production.” 

The researchers tested two types of the mutated gene and directly connected it with removing ABHD5/CGI-58’s part in assembling the virus.

“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,” according to the study. The lipid flux that comes as a result of this process is also part of HCV’s assembly and release in creating the HCV lipo-viral particle, which is how the virus travels through the blood, researchers noted.

Experiments with ABHD5 did not show a link to viral genome replication or cell entry. Localization of ABHD5 was pinpointed to lipid droplet surfaces and areas of cell secretion – the same sites where HCV assembles.

“Our data specifically link ABHD5 ability to trigger a lipid flux with its proviral effect on both HCV assembly and release,” the researchers concluded. “Our findings indicate that ABHD5 supports HCV production by triggering the mobilization of the lipid droplet lipid stores for the assembly and release of infectious lipo-viro-particles. They shed light on host determinants of HCV and VLDL morphogenesis, on the role of ABHD5 in hepatocytes and the etiology of the liver dysfunctions observed in the Chanarin-Dorfman patients.”

Reference

1. Vieyres G, Welsch K, Gerold G et al. ABHD5/CGI-58, the Chanarin-Dorfman Syndrome protein, mobilizes lipid stores for hepatitis C virus production. PLoS Pathog. 2016;12(4):e1005568. doi:10.1371/journal.ppat.1005568. Published Online April 28, 2016. Accessed June 2, 2016.