Hepatitis C virus infection activates a novel NF-κB-independent function of IKKα in lipid droplet biogenesis and viral assembly

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIDDK	VIROL/MICRO-14

Authors

• Q Li
• V Pène
• S Krishnamurthy
• TJ Liang

Abstract

Hepatitis C virus (HCV) interacts extensively with host factors to establish productive and persistent infection. Our recent genome-wide small interfering RNA (siRNA) screen demonstrated that IKKα is required for HCV propagation (Li et al., 2009 PNAS). Here we describe a novel NF-κB-independent and kinase-mediated function of IKKα in HCV assembly. siRNA silencing of IKKα markedly reduced core-associated lipid droplets and expression of lipogenic genes in HCV-infected cells. HCV infection, through the combined action of HCV pathogen-associated molecular pattern (PAMP) and NS3/4A, activates NF-κB-inducing kinase (NIK) and IKKα, which translocates to the nucleus and induces a CREB-binding protein (CBP)-mediated transcriptional program involving SREBP1. Silencing of SREBP1 and several SREBP1-regulated lipogenic genes exhibited the same phenotype as IKKα silencing in HCV infected cells. Chemical inhibitors of IKK suppress HCV infection and IKKα-induced lipogenic pathway. Our study demonstrates that HCV commands a novel mechanism to its own advantage by exploiting the intrinsic innate immunity and hijacking the lipid metabolism, both of which likely contribute to the high persistent rate and the pathological hallmark of steatosis in HCV infection.

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