Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets

EMBO J. 2002 Aug 1;21(15):3980-8. doi: 10.1093/emboj/cdf414.

Abstract

Hepatitis C virus (HCV) is the major causative pathogen associated with liver cirrhosis and hepatocellular carcinoma. The virus has a positive-sense RNA genome encoding a single polyprotein with the virion components located in the N-terminal portion. During biosynthesis of the polyprotein, an internal signal sequence between the core protein and the envelope protein E1 targets the nascent polypeptide to the endoplasmic reticulum (ER) membrane for translocation of E1 into the ER. Following membrane insertion, the signal sequence is cleaved from E1 by signal peptidase. Here we provide evidence that after cleavage by signal peptidase, the signal peptide is further processed by the intramembrane-cleaving protease SPP that promotes the release of core protein from the ER membrane. Core protein is then free for subsequent trafficking to lipid droplets. This study represents an example of a potential role for intramembrane proteolysis in the maturation of a viral protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Cell Line / virology
  • Cricetinae
  • Endoplasmic Reticulum / metabolism
  • Hepacivirus / metabolism*
  • Inclusion Bodies / metabolism
  • Kidney
  • Lipid Metabolism
  • Membrane Proteins / metabolism*
  • Mesocricetus
  • Molecular Sequence Data
  • Protein Sorting Signals / genetics
  • Protein Sorting Signals / physiology*
  • Protein Transport
  • Serine Endopeptidases / physiology
  • Viral Core Proteins / metabolism*
  • Viral Envelope Proteins / analysis
  • Viral Envelope Proteins / metabolism*

Substances

  • E1 protein, Hepatitis C virus
  • Membrane Proteins
  • Protein Sorting Signals
  • Viral Core Proteins
  • Viral Envelope Proteins
  • nucleocapsid protein, Hepatitis C virus
  • glycoprotein E2, Hepatitis C virus
  • Serine Endopeptidases
  • type I signal peptidase