Molecular mechanism of HCV-induced formation of large lipid droplets and virus life cycle

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07514
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Kobe University
• Principal Investigator: Shoji Ikuo 神戸大学, 医学研究科, 教授 (40356241)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: HCV / JNK / AIP4 / ADRP / SPG20 / 脂肪滴 / 肝脂肪化

Outline of Final Research Achievements

We focused on these 3 topics.1. HCV infection induced JNK activation and AIP4 phosphorylation 2. ADRP ubiquitination by E3 ligase AIP4. ADRP ubiquitination by peridroplet proteins and AIP4. 3. analysis of the mechanism of ADRP ubiquitination by peridroplet proteins and AIP4. HCV JNK activation caused phosphorylation and activation of AIP4. immunofluorescence staining of HCV-infected cells revealed that ADRP was mainly localized around LDs. Taken together, these results suggest that NS3/4A protease specifically cleaves SPG20 and inhibits Itch-mediated ubiquitin-dependent degradation of LD-associated ADRP, thereby promoting the formation of large LDs.

Free Research Field

ウイルス学

Academic Significance and Societal Importance of the Research Achievements

HCV感染患者の肝に脂肪化が発症することは臨床上よく知られ、HCV感染による脂質代謝系の変化が詳細に解析されてきた。しかし、HCV感染初期に肝細胞で脂肪滴（Lipid droplet, LD)が肥大化し、肥大脂肪滴が維持される分子機構は不明であった。しかし、本研究により、HCV感染で早期に肝細胞に脂肪滴形成が誘導される分子機構が明らかとなった。HCV感染による肝脂肪化に対する治療法開発へとつながることが期待される。