Nari Kim1, Min-Jung Kim1, Pil Soo Sung2, Yong Chul Bae3, Eui-Cheol Shin2 & Joo-Yeon Yoo1
1 Division of Molecular and Life Sciences, Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
2 Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Republic of Korea.
3 Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea.
Correspondence to : Joo-Yeon Yoo
Hepatitis C virus (HCV) utilizes autophagy to promote its propagation. Here we show the autophagy-mediated suppression of HCV replication via the endoplasmic reticulum (ER) protein SCOTIN. SCOTIN overexpression inhibits HCV replication and infectious virion production in cells infected with cell culture-derived HCV. HCV nonstructural 5A (NS5A) protein, which is a critical factor for HCV RNA replication, interacts with the IFN-β-inducible protein SCOTIN, which transports NS5A to autophagosomes for degradation. Furthermore, the suppressive effect of SCOTIN on HCV replication is impaired in both ATG7-silenced cells and cells treated with autophagy or lysosomal inhibitors. SCOTIN does not affect the overall flow of autophagy; however, it is a substrate for autophagic degradation. The physical association between the transmembrane/proline-rich domain (TMPRD) of SCOTIN and Domain-II of NS5A is essential for autophagosomal trafficking and NS5A degradation. Altogether, our findings suggest that IFN-β-induced SCOTIN recruits the HCV NS5A protein to autophagosomes for degradation, thereby restricting HCV replication.