Interferon-inducible protein SCOTIN interferes with HCV replication through the autolysosomal degradation of NS5A

Nat Commun. 2016 Feb 12:7:10631. doi: 10.1038/ncomms10631.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / immunology*
  • Autophagy / immunology*
  • Cell Line, Tumor
  • Fluorescent Antibody Technique
  • Hepacivirus / metabolism*
  • Hepacivirus / physiology
  • Hepatocytes*
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Interferon-beta / immunology*
  • Membrane Proteins / immunology*
  • Phagosomes / immunology*
  • RNA, Viral / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Viral Nonstructural Proteins / metabolism*
  • Virus Replication / physiology*

Substances

  • Apoptosis Regulatory Proteins
  • Membrane Proteins
  • RNA, Viral
  • SHISA5 protein, human
  • Viral Nonstructural Proteins
  • Interferon-beta
  • NS-5 protein, hepatitis C virus