GRIM-19 Restricts HCV Replication by Attenuating Intracellular Lipid Accumulation

• Published in: Frontiers in microbiology Vol. 8; p. 576
• Main Authors: Kim, Jung-Hee, Sung, Pil S, Lee, Eun B, Hur, Wonhee, Park, Dong J, Shin, Eui-Cheol, Windisch, Marc P, Yoon, Seung K
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 11.04.2017
• Subjects: Microbiology; viral replication; hepatitis C virus; lipogenesis; anti-viral host factor; intracellular lipid accumulation
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2017.00576

Gene-associated with retinoid-interferon-induced mortality 19 (GRIM-19) targets multiple signaling pathways involved in cell death and growth. However, the role of GRIM-19 in the pathogenesis of hepatitis virus infections remains unexplored. Here, we investigated the restrictive effects of GRIM-19 on the replication of hepatitis C virus (HCV). We found that GRIM-19 protein levels were reduced in HCV-infected Huh7 cells and Huh7 cells harboring HCV replicons. Moreover, ectopically expressed GRIM-19 caused a reduction in both intracellular viral RNA levels and secreted viruses in HCVcc-infected cell cultures. The restrictive effect on HCV replication was restored by treatment with siRNA against GRIM-19. Interestingly, GRIM-19 overexpression did not alter the level of phosphorylated STAT3 or its subcellular distribution. Strikingly, forced expression of GRIM-19 attenuated an increase in intracellular lipid droplets after oleic acid (OA) treatment or HCVcc infection. GRIM-19 overexpression abrogated fatty acid-induced upregulation of sterol regulatory element-binding transcription factor-1 (SREBP-1c), resulting in attenuated expression of its target genes such as fatty acid synthase (FAS) and acetyl CoA carboxylase (ACC). Treatment with OA or overexpression of SREBP-1c in GRIM-19-expressing, HCVcc-infected cells restored HCV replication. Our results suggest that GRIM-19 interferes with HCV replication by attenuating intracellular lipid accumulation and therefore is an anti-viral host factor that could be a promising target for HCV treatment.