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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.

Titel:	Very-long-chain fatty acid metabolic capacity of 17-beta-hydroxysteroid dehydrogenase type 12 (HSD17B12) promotes replication of hepatitis C virus and related flaviviruses.
Autor/in / Beteiligte Person:	Mohamed, B ; Mazeaud, C ; Baril, M ; Poirier, D ; Sow, AA ; Chatel-Chaix, L ; Titorenko, V ; Lamarre, D
Link:	Full Text Finder (Volltext)
Zeitschrift:	Scientific reports, Jg. 10 (2020-03-04), Heft 1, S. 4040
Veröffentlichung:	London : Nature Publishing Group, copyright 2011-, 2020
Medientyp:	academicJournal
ISSN:	2045-2322 (electronic)
DOI:	10.1038/s41598-020-61051-w
Schlagwort:	17-Hydroxysteroid Dehydrogenases genetics Animals Chlorocebus aethiops HeLa Cells Hep G2 Cells Hepatitis C genetics Humans Vero Cells Virus Replication genetics 17-Hydroxysteroid Dehydrogenases metabolism Hepacivirus physiology Hepatitis C enzymology Oleic Acid pharmacology Virus Replication drug effects
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Sci Rep] 2020 Mar 04; Vol. 10 (1), pp. 4040. <i>Date of Electronic Publication: </i>2020 Mar 04. MeSH Terms: 17-Hydroxysteroid Dehydrogenases / metabolism ; Hepacivirus / physiology ; Hepatitis C / enzymology ; Oleic Acid / pharmacology ; Virus Replication / *drug effects ; 17-Hydroxysteroid Dehydrogenases / genetics ; Animals ; Chlorocebus aethiops ; HeLa Cells ; Hep G2 Cells ; Hepatitis C / genetics ; Humans ; Vero Cells ; Virus Replication / genetics References: Ravindran, M. S., Bagchi, P., Cunningham, C. N. & Tsai, B. Opportunistic intruders: how viruses orchestrate ER functions to infect cells. Nat. Rev. Microbiol. 14, 407–420 (2016). (PMID: 10.1038/nrmicro.2016.602726576827265768) ; Chatel-Chaix, L. & Bartenschlager, R. Dengue virus- and hepatitis C virus-induced replication and assembly compartments: the enemy inside–caught in the web. J. 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Very-long-chain fatty acid metabolic capacity of 17-beta-hydroxysteroid dehydrogenase type 12 (HSD17B12) promotes replication of hepatitis C virus and related flaviviruses.