Abstract
Flaviviridae infections represent a major global health burden. By deciphering mechanistic aspects of hepatitis C virus (HCV)-host interactions, one could discover common strategy for inhibiting the replication of related flaviviruses. By elucidating the HCV interactome, we identified the 17-beta-hydroxysteroid dehydrogenase type 12 (HSD17B12) as a human hub of the very-long-chain fatty acid (VLCFA) synthesis pathway and core interactor. Here we show that HSD17B12 knockdown (KD) impairs HCV replication and reduces virion production. Mechanistically, depletion of HSD17B12 induces alterations in VLCFA-containing lipid species and a drastic reduction of lipid droplets (LDs) that play a critical role in virus assembly. Oleic acid supplementation rescues viral RNA replication and production of infectious particles in HSD17B12 depleted cells, supporting a specific role of VLCFA in HCV life cycle. Furthermore, the small-molecule HSD17B12 inhibitor, INH-12, significantly reduces replication and infectious particle production of HCV as well as dengue virus and Zika virus revealing a conserved requirement across Flaviviridae virus family. Overall, the data provide a strong rationale for the advanced evaluation of HSD17B12 inhibition as a promising broad-spectrum antiviral strategy for the treatment of Flaviviridae infections.
Highlights
Flaviviridae infections represent a major global health burden
Upon hepatitis C virus (HCV) infection, we showed that a fraction of endogenous HSD17B12 overlaps viral replication and assembly sites as revealed by the co-staining with anti-HSD17B12 and anti-double-strand RNA or anti-core antibodies in fluorescence microscopy, respectively
The data support the hijacking of HSD17B12 at membranous web (MW) and further suggest that this promotes de novo synthesis of very-long-chain fatty acid (VLCFA) and derived lipids for the benefit of HCV replication
Summary
Flaviviridae infections represent a major global health burden. By deciphering mechanistic aspects of hepatitis C virus (HCV)-host interactions, one could discover common strategy for inhibiting the replication of related flaviviruses. Fatty acids are constituents of triglycerides, phospholipids and complex lipids, and their synthesis have long been identified as a requirement for the replication of many viruses including Flaviviridae[13,14,15,16,17] They contribute to the structural integrity of membranes, energy production and storage, and generation of LDs. Saturated fatty acids up to 16 carbon atoms (C16) in length are synthesized in the cytosol by the multifunctional protein fatty acid synthase (FASN), which utilizes acetyl-CoA (C2:0-CoA), malonyl-CoA and NADPH to elongate fatty acids through a two-carbon increment process. The data support a contribution of de novo VLCFA synthesis for Flaviviridae virus infections and provide a strong rationale to explore the broad-spectrum antiviral potential of targeting HSD17B12 to treat and/or prevent RNA virus infections
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
