Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance

Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.
Journal of Virology (Impact Factor: 4.65). 03/2012; 86(11):6315-22. DOI: 10.1128/JVI.00050-12
Source: PubMed

ABSTRACT Hepatitis C virus (HCV) infection significantly increases the prevalence of type 2 diabetes mellitus (T2DM). Insulin receptor substrate 1 (IRS-1) plays a key role in insulin signaling, thus enabling metabolic regulation in mammalian cells. We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. Inhibition of IRS-1 expression was observed in HCV-infected hepatocytes compared to that in a mock-infected control. The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. Interestingly, the phosphoS6K1 level was higher in HCV-infected hepatocytes, suggesting a novel mechanism for IRS-1 inhibition. Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance.

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    • "Indeed, human papillomavirus virus 16 was shown to induce mammalian TOR (mTOR) through upregulation of growth factor receptor signalling (Surviladze et al., 2013), while vaccinia virus upregulates PI3K (Soares et al., 2009). Furthermore, hepatitis C virus was found to similarly induce the mTOR/S6K axis by inhibiting the TSC1/TSC2 complex (Bose et al., 2012), which negatively regulates mTOR signalling upstream of the protein Rheb. In human cytomegalovirus (HCMV)infected cells, mTOR signalling was also maintained, although this virus induces several host metabolic stresses, such as endoplasmic reticulum (ER) stress, hypoxia and AA starvation (Clippinger et al., 2011), suggesting that mTOR signalling persistence in HCMVinfected cells is likely the result of an active manipulation. "
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