Centre de Recherche du CHUM (CRCHUM) et Faculté de Médecine, Université de Montréal, Montréal, Canada.
Pharmacology Department, Medical Research Division, National Research Centre, Cairo, Egypt.
Sci Rep. 2020 Mar 4;10(1):4040. doi: 10.1038/s41598-020-61051-w.
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.
黄病毒感染是全球主要的健康负担。通过解析丙型肝炎病毒（HCV）-宿主相互作用的机制方面，人们可以发现抑制相关黄病毒复制的共同策略。通过阐明 HCV 相互作用组，我们发现 17-β-羟类固醇脱氢酶 12（HSD17B12）是非常长链脂肪酸（VLCFA）合成途径的人类枢纽和核心相互作用蛋白。在这里，我们表明 HSD17B12 敲低（KD）会损害 HCV 复制并减少病毒粒子的产生。从机制上讲，HSD17B12 的耗竭会导致含有 VLCFA 的脂质种类发生变化，并使在病毒组装中起关键作用的脂滴（LDs）急剧减少。油酸补充可挽救 HSD17B12 耗尽细胞中的病毒 RNA 复制和感染性颗粒的产生，这支持了 VLCFA 在 HCV 生命周期中的特定作用。此外，小分子 HSD17B12 抑制剂 INH-12 可显著降低 HCV 以及登革热病毒和寨卡病毒的复制和感染性颗粒的产生，这表明 Flaviviridae 病毒家族存在保守的需求。总体而言，这些数据为 HSD17B12 抑制作为治疗 Flaviviridae 感染的有前途的广谱抗病毒策略的深入评估提供了强有力的依据。
