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SMAD About Hepatitis C Virus Cell Entry and Liver Disease
Che Colpitts, Thomas Baumert
To cite this version:
Che Colpitts, Thomas Baumert. SMAD About Hepatitis C Virus Cell Entry and Liver Disease. Gas- troenterology, WB Saunders, 2017, 152 (1), pp.21-23. �10.1053/j.gastro.2016.11.029�. �hal-02373065�
SMAD About Hepatitis C Virus Cell Entry and Liver Disease
Che C. Colpitts and
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques and Université de Strasbourg, Strasbourg, France
Thomas F. Baumert
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques and Université de Strasbourg and Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hopitaux, Universitaires de Strasbourg, Strasbourg, France
Hepatitis C virus (HCV) remains a major global health burden, with approximately 150 million people persistently infected. Chronically infected individuals are at increased risk for severe progressive liver disease, including cirrhosis and hepatocellular carcinoma.
Importantly, the burden of HCV-associated disease will likely remain substantial in the era of oral direct-acting antivirals, even in high-resource countries such as the United States.1 The risk for hepatocellular carcinoma can persist after viral cure, in particular when fibrosis is already established.2 HCV interacts with an extensive network of host factors during infection of hepatocytes, which may provide novel targets for host-directed antivirals.
Furthermore, a comprehensive identification of HCV host dependencies is crucial to better understand the pathogenesis of HCV-induced liver disease biology and to identify strategies for the prevention of hepatocellular carcinoma. In this issue of Gastroenterology, Zhang et al3 characterize the role of SMAD6 in the regulation of HCV entry and uncover a new role for inhibitory SMADs (I-SMADs) in viral pathogenesis.
HCV entry is a highly coordinated process, requiring interaction with a number of cellular factors. After binding to heparan sulfate proteoglycans (HSPGs) and lipoprotein receptors, including low-density lipoprotein receptor and scavenger receptor class B1 type I, viral particles are endocytosed and fuse in early endosomes. Although several host proteins have been identified as regulatory factors, the detailed regulation of the HCV entry process is only partially understood.4 Zhang et al3 follow up on their previous identification of SMAD6 as an HCV host factor.5 Transcriptomics analysis revealed that silencing of SMAD6 decreased the expression of HSPGs, with a corresponding reduction in cell surface expression of heparan sulfate.3 Furthermore, SMAD6 knockdown decreased expression of cholesterol uptake receptors and HCV entry factors, including low-density lipoprotein receptor and scavenger receptor class B1 type I. In contrast, exogenous expression of SMAD6 was shown to up-regulate the expression of HSPGs and cholesterol uptake receptors.3 By modulating
Reprint requests, Address requests for reprints to: Thomas F. Baumert, MD, Inserm U1110, 3 Rue Koeberlé, 67000 Strasbourg,
HHS Public Access
Author manuscript
Gastroenterology. Author manuscript; available in PMC 2017 February 17.
Published in final edited form as:
Gastroenterology. 2017 January ; 152(1): 21–23. doi:10.1053/j.gastro.2016.11.029.
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the expression of viral entry factors, SMAD6 regulates the ability of HCV to infect cells (Figure 1).
SMAD6 is an inhibitory I-SMAD within the broader family of SMAD proteins. These proteins play important roles in signal transduction, particularly in regulating the transforming growth factor (TGF)-β pathway. Whereas the receptor-regulated SMADs, including SMAD2,SMAD3,SMAD4, and SMAD5, positively regulate TGF-β signaling, the I-SMADs SMAD6 and SMAD7 act as antagonists of the this pathway. I-SMADs also act as transcriptional co-activators, given their role in activating transcription of genes encoding HSPGs and cholesterol uptake receptors.3 Because I-SMADs are induced by the bone morphogenetic protein (BMP)/TGF-β signaling pathway, the cytokines BMP6 and BMP7 induce expression of I-SMADs to increase HCV entry factor expression.3 Interestingly, HSPGs themselves are BMP co-receptors and contribute to the regulation of BMP/TGF-β signaling.6 This study, therefore, opens avenues for further studies to dissect the interplay between I-SMADs, BMPs, and HSPGs in the context of chronic HCV infection, which may identify novel antiviral or chemo-preventive strategies for HCV-induced liver disease. For example, BMP6 inhibits hepatic fibrosis in nonalcoholic fatty liver disease7 and may represent a promising therapeutic target. Interestingly, SMAD7 was proposed previously as a candidate for novel therapeutic approaches to limit TGF-β–mediated fibrogenesis arising during chronic hepatitis B virus infection8 and may provide a strategy to broadly ameliorate the fibrosis caused by multiple etiologies in human hepatic diseases.
HCV infection up-regulates the expression of I-SMADs in hepatocytes via activation of nuclear factor-κB,3 thereby increasing expression of HSPGs and cholesterol uptake receptors (Figure 1). Increased I-SMAD and HSPG messenger RNA expression was observed in HCV-infected liver biopsies, 3 confirming relevance in patients. Increased cholesterol uptake into infected cells likely enhances viral replication and assembly steps, given the critical roles of cholesterol in the viral life cycle.9 The modulation of signaling pathways or metabolic processes impacted by HSPGs may also contribute to enhanced viral replication. Furthermore, increased HSPG expression on the surface of infected hepatocytes may concentrate the virus in the liver microenvironment to facilitate the infection of neighboring cells.
The HCV-induced increase in I-SMAD expression likely has profound implications for HCV disease biology and pathogenesis, given the multiple roles of I-SMADs in regulating HSPG expression, cholesterol uptake, and TGF-β signaling. HSPGs play key roles in cell adhesion and migration, as well as in binding to cytokines and growth factors and regulating growth factor receptors to modulate downstream signal transduction.10 The HCV-induced I-SMAD–
mediated up-regulation of HSPG expression may well impact hepatocyte proliferation or migration, contributing to hepatocarcinogenesis or migration of cancerous cells. Similarly, aberrant regulation of the TGF-β pathway may impact cellular proliferation, differentiation, death, and migration in the liver, as TGF-β and other growth factors regulate these processes to maintain tissue homeostasis. It would be interesting to evaluate potential correlations between HCV-induced modulation of I-SMAD–regulated processes and the severity of liver disease in chronically infected patients.
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Zhang et al3 now identify a new role for I-SMADs as regulators of lipid metabolism in the liver. By inducing the expression of HSPGs11 and lipoprotein uptake receptors, I-SMADs contribute to the uptake of cholesterol and lipids into the liver. In the context of HCV infection, this function of I-SMADs may contribute to steatosis. Furthermore, given the role of BMP6 as a regulator of iron uptake12 and the fact that iron metabolism seems to be dysregulated during chronic hepatitis C infection,13 I-SMADs and the BMP/TGF-β pathway suggest a link between iron homeostasis and lipid metabolism in HCV-infected cells. Further mechanistic studies are warranted, since they may provide targets to limit steatosis and iron accumulation in the liver of infected patients. Because the TGF-β pathway is also involved in inflammation and immune regulation, it would be interesting to further probe the roles of I-SMADs in HCV-induced inflammation, a key contributor to fibrosis.
Overall, Zhang et al3 identify a novel regulatory mechanism for HCV entry, with implications for HCV pathogenesis and liver disease. Modulation of the activity of I- SMADs or related factors such as BMP6 could prevent HCV infection by modulation of entry factor expression. More importantly, these findings may provide novel perspectives to prevent or limit the development of HCV-induced liver disease to improve the outlook for chronically infected patients.
Acknowledgments
TFB acknowledges support from the National Institutes of Health (NIAID U19 AI123862-01), the European Union (ERC-2014-AdG-671231-HEPCIR, FP7 HepaMAb, EU H2020 HepCAR), the French Cancer Agency (ARC IHU201301187), and ANR (LABEX ANR-10-LAB-28). CCC acknowledges fellowships from the Canadian Institutes of Health Research (201411MFE-338606-245517) and the Canadian Network on Hepatitis C.
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Figure 1.
Proposed role of I-SMADs during hepatitis C virus (HCV) infection according to Zhang et al.3 I-SMADs, induced by HCV infection, transcriptionally regulate expression of HCV entry factors, including HSPGs and cholesterol uptake receptors. HSPGs, heparan sulfate proteoglycans; SR-BI, scavenger receptor class B type I; LDLR, low density lipoprotein receptor; NF-κB, nuclear factor kappa B; TGF-β, transforming growth factor beta; I- SMADs, inhibitory SMADs.
