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Mol. Cells

Published online December 15, 2021

© The Korean Society for Molecular and Cellular Biology

Hepatitis C Virus Nonstructural 5A Protein Interacts with Telomere Length Regulation Protein: Implications for Telomere Shortening in Patients Infected with HCV

Yun-Sook Lim1 , Men T.N. Nguyen2 , Thuy X. Pham1 , Trang T.X. Huynh1 , Eun-Mee Park3 , Dong Hwa Choi4 , Sang Min Kang5 , Dongseob Tark5 , and Soon B. Hwang1,2,*

1Laboratory of RNA Viral Diseases, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea, 2Ilsong Institute of Life Science, Hallym University, Seoul 07247, Korea, 3Center for Immunology and Pathology, National Institute of Health, Korea Center for Disease Control & Prevention, Cheongju 28159, Korea, 4Biocenter, Gyeonggido Business & Science Accelerator, Suwon 16229, Korea, 5Laboratory for Infectious Disease Prevention, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea

Correspondence to : sbhwang@jbnu.ac.kr

Received: June 23, 2021; Revised: October 17, 2021; Accepted: October 27, 2021

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Hepatitis C virus (HCV) is a major cause of chronic liver disease and is highly dependent on cellular proteins for viral propagation. Using protein microarray analysis, we identified 90 cellular proteins as HCV nonstructural 5A (NS5A) interacting partners, and selected telomere length regulation protein (TEN1) for further study. TEN1 forms a heterotrimeric complex with CTC and STN1, which is essential for telomere protection and maintenance. Telomere length decreases in patients with active HCV, chronic liver disease, and hepatocellular carcinoma. However, the molecular mechanism of telomere length shortening in HCV-associated disease is largely unknown. In the present study, protein interactions between NS5A and TEN1 were confirmed by immunoprecipitation assays. Silencing of TEN1 reduced both viral RNA and protein expression levels of HCV, while ectopic expression of the siRNA-resistant TEN1 recovered the viral protein level, suggesting that TEN1 was specifically required for HCV propagation. Importantly, we found that TEN1 is re-localized from the nucleus to the cytoplasm in HCV-infected cells. These data suggest that HCV exploits TEN1 to promote viral propagation and that telomere protection is compromised in HCV-infected cells. Overall, our findings provide mechanistic insight into the telomere shortening in HCV-infected cells.

Keywords hepatitis C virus, NS5A, protein microarray, telomere shortening, TEN1

Article

On-line First

Mol. Cells

Published online December 15, 2021

Copyright © The Korean Society for Molecular and Cellular Biology.

Hepatitis C Virus Nonstructural 5A Protein Interacts with Telomere Length Regulation Protein: Implications for Telomere Shortening in Patients Infected with HCV

Yun-Sook Lim1 , Men T.N. Nguyen2 , Thuy X. Pham1 , Trang T.X. Huynh1 , Eun-Mee Park3 , Dong Hwa Choi4 , Sang Min Kang5 , Dongseob Tark5 , and Soon B. Hwang1,2,*

1Laboratory of RNA Viral Diseases, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea, 2Ilsong Institute of Life Science, Hallym University, Seoul 07247, Korea, 3Center for Immunology and Pathology, National Institute of Health, Korea Center for Disease Control & Prevention, Cheongju 28159, Korea, 4Biocenter, Gyeonggido Business & Science Accelerator, Suwon 16229, Korea, 5Laboratory for Infectious Disease Prevention, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea

Correspondence to:sbhwang@jbnu.ac.kr

Received: June 23, 2021; Revised: October 17, 2021; Accepted: October 27, 2021

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Hepatitis C virus (HCV) is a major cause of chronic liver disease and is highly dependent on cellular proteins for viral propagation. Using protein microarray analysis, we identified 90 cellular proteins as HCV nonstructural 5A (NS5A) interacting partners, and selected telomere length regulation protein (TEN1) for further study. TEN1 forms a heterotrimeric complex with CTC and STN1, which is essential for telomere protection and maintenance. Telomere length decreases in patients with active HCV, chronic liver disease, and hepatocellular carcinoma. However, the molecular mechanism of telomere length shortening in HCV-associated disease is largely unknown. In the present study, protein interactions between NS5A and TEN1 were confirmed by immunoprecipitation assays. Silencing of TEN1 reduced both viral RNA and protein expression levels of HCV, while ectopic expression of the siRNA-resistant TEN1 recovered the viral protein level, suggesting that TEN1 was specifically required for HCV propagation. Importantly, we found that TEN1 is re-localized from the nucleus to the cytoplasm in HCV-infected cells. These data suggest that HCV exploits TEN1 to promote viral propagation and that telomere protection is compromised in HCV-infected cells. Overall, our findings provide mechanistic insight into the telomere shortening in HCV-infected cells.

Keywords: hepatitis C virus, NS5A, protein microarray, telomere shortening, TEN1

Mol. Cells
Dec 31, 2021 Vol.44 No.12, pp. 861~919
COVER PICTURE
Structure of the fly peripheral neurons in the fly head. Flies have basic sensory organs including eyes for vision, antennae and maxillary palps for olfaction, and proboscis (magenta) for gustation which can be labelled with monoclonal antibody 22C10. The figure is a 3D reconstructed image with 30 slices of confocal sections with 3 μm interval. It shows that the proboscis is required for sensing attractive carboxylic acids such as glycolic acid, citric acid, and lactic acid (Shrestha and Lee, pp. 900-910).

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