Hepatitis C virus infection activates an innate pathway Involving IKK-α in lipogenesis and viral assembly

Qisheng Li, Véronique Pène, Siddharth Krishnamurthy, Helen Cha & T Jake Liang

Nature Medicine (2013) 19, 722–729

Speaker: Yi-Sheng Kao (高宜聲)                           Time: 14:10~15:00, Nov.13, 2013

Commentator: Dr. Kung-Chia Young (楊孔嘉 老師)       Place: Room 601

Abstract:

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease with a unique pathological feature: the accumulation of cytosolic lipid droplets (LDs) resulting in steatosis. Upon infection, HCV utilizes lipid droplets as platforms for viral assembly (1). However, the mechanism for accumulation of LDs remains unclear. The authors’ recent genome-wide siRNA screen demonstrated that IκB kinase-α (IKK-α) is a crucial host factor for HCV (2). Therefore, the authors tried to investigate how IKK-α participates in HCV life cycle. They found that IKK-α depletion inhabits LDs formation, especially in the late stage of HCV life cycle, suggesting that IKK-α is important for assembling and producing mature HCV viral particle. Next, in order to define the mechanism of the HCV-responsive activation of IKK-α and induction of lipogenesis, author used HCV 3’untranslated region (3’UTR), which has been identified as a HCV pathogen-associated molecular patterns (PAMP) to induce LD formation. They revealed that 3’UTR with DEAD box polypeptide 3, X-linked (DDX3X) leads to IKK-α activation. Activated IKK-α will translocate to the nucleus, and induce a sterol regulatory element-binding proteins (SREBPs) expression through transcription factor CBP/p300.This HCV activated IKK-α pathway can induce lipogenic genes and LD formation, and is NF-ĸB-independent. IKK-α inhibitors suppress both HCV induction lipogenesis and infection. In conclusion, this paper provide a direct functional link between HCV infection, inflammation, innate immunity and hepatic lipid metabolism. More importantly, results presented here offer a novel concept approach for HCV therapeutic strategy.

References:

1.     Miyanari, Y. et al. The lipid droplet is an important organelle for hepatitis C virus production. Nat. Cell. Biol. (2007) 9, 1089–1097.

2.     Li, Q. et al. A genome-wide genetic screen for host factors required for hepatitis C virus propagation. Proc. Natl. Acad. Sci. USA. (2009)106, 16410–16415.