TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis.

Abstract

Signal-peptide peptidase (SPP) is an intramembrane protease that participates in the production of the mature core protein of hepatitis C virus (HCV). Here we show that SPP inhibition reduces the production of infectious HCV particles and pathogenesis. The immature core protein produced in SPP-knockout cells or by treatment with an SPP inhibitor is quickly degraded by the ubiquitin-proteasome pathway. Oral administration of the SPP inhibitor to transgenic mice expressing HCV core protein (CoreTg) reduces the expression of core protein and ameliorates insulin resistance and liver steatosis. Moreover, the haploinsufficiency of SPP in CoreTg has similar effects. TRC8, an E3 ubiquitin ligase, is required for the degradation of the immature core protein. The expression of the HCV core protein alters endoplasmic reticulum (ER) distribution and induces ER stress in SPP/TRC8 double-knockout cells. These data suggest that HCV utilizes SPP cleavage to circumvent the induction of ER stress in host cells.

• Authors: Sayaka Aizawa, Toru Okamoto, Yukari Sugiyama, Takahisa Kouwaki, Ayano Ito, Tatsuya Suzuki, Chikako Ono, Takasuke Fukuhara, Masahiro Yamamoto, Masayasu Okochi, Nobuhiko Hiraga, Michio Imamura, Kazuaki Chayama, Ryosuke Suzuki, Ikuo Shoji, Kohji Moriishi, Kyoji Moriya, Kazuhiko Koike, Yoshiharu Matsuura
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 11379 (May 04 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27142248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ubiquitin
• Viral Core Proteins
• nucleocapsid protein, Hepatitis C virus
• Ubiquitin-Protein Ligases
• Aspartic Acid Endopeptidases
• signal peptide peptidase
• Proteasome Endopeptidase Complex

Topics

• Animals
• Aspartic Acid Endopeptidases (genetics, metabolism)
• Disease Models, Animal
• Endoplasmic Reticulum Stress (genetics)
• Fatty Liver (genetics, metabolism, pathology)
• Gene Expression Regulation
• Haploinsufficiency
• Hepacivirus (pathogenicity, physiology)
• Hepatitis C (genetics, metabolism, pathology)
• Host-Pathogen Interactions
• Humans
• Insulin Resistance
• Male
• Mice
• Mice, Transgenic
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis
• Signal Transduction
• Ubiquitin (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Viral Core Proteins (genetics, metabolism)
• Virus Replication