Life science
Medical care, Drug development

Hepatitis C virus modulates signal peptide peptidase
to alter host protein processing
Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases
Professor Toru Okamoto
https://researchmap.jp/TOKAMOTOLife science

Abstract
Hepatitis C virus (HCV) evades immune surveillance to induce
chronic infection; however, how HCV-infected hepatocytes affectimmune cells and evade immune recognition remains unclear. We
demonstrate that HCV core protein interfered with the maturation ofMHC class I molecules catalyzed by the signal peptide peptidase(SPP) and induced their degradation via HMG-CoA reductase
degradation 1 homolog, thereby impairing antigen presentation toCD8+ T cells. The expression of MHC class I in the livers of chronic hepatitis C patients was impaired but was restored in patientsachieving sustained virological response. Finally, we show that thehuman cytomegalovirus US2 protein, possessing a transmembraneregion structurally similar to the HCV core protein, targets SPP toimpair MHC class I molecule expression. Thus, SPP represents apotential target for the impairment of MHC class I molecules byDNA and RNA viruses.

▍ Significance of the research and Future perspective
Our study revealed a novel molecular mechanism by which theseviruses target an important component of the human immune system, MHC class I molecules, to interfere with the proper immune
response. These findings could help with development of novel
therapies against persistent infection caused by these viruses.

▍ Background & Results
HCV infection becomes chronic in approximately 80% of patients. Antiviral therapies exist and can improve the patients’ conditions, but liver disease, and consequentially the formation of livercancer, is not sufficiently mitigated by this therapeutic approach.
It is thus important to understand how HCV manages to evade thehost’s immune system in the first place to become chronically established, to help researchers develop novel and better therapies
against the disease.
At the molecular level, HCV produces a single protein in infected cells that is then split into ten individual proteins. One of these
proteins is the HCV core protein, which for stable function requires
the action of one of the host cell’s proteins, the signal peptide
peptidase (SPP). Researchers know that blocking SPP results in
the HCV core protein being broken down, and thus suppresses theproduction of infectious HCV particles. However, the ways in which
the core protein affects the host’s immune system have remained
unclear – until now.
We employed a human liver cell line to understand how the HCVcore protein, SPP and MHC class I proteins interact. We foundthat SPP is required for the production of MHC class I molecules
to enable a proper immune response in liver cells. However, inthe presence of the HCV core protein, SPP cannot properly interact with MHC class I proteins, which are then degraded via theactions of another protein, HMG-CoA reductase degradation 1
homolog (HRD1). As a result, cellular presentation of viral particles
to immune cells is impaired and the infection continues to becomechronic.
We then asked if this might be a common mechanism to evadethe host’s immune system in other virus infections. They foundthat a protein produced by Human cytomegalovirus (HCMV), US2protein, is structurally similar to the HCV core protein and similarly
induces degradation of MHC class I proteins by targeting SPP.
Thus, SPP represents a potential target for the impairment ofMHC class I molecules by DNA and RNA viruses.

P a t e n t
Tr e a t i s e

Hirano, Junki; Yoshio, Sachiyo; Sakai, Yusuke et al. Hepatitis C virus modulates signal peptide peptidase to alter host protein processing. Proc Natl Acad
Sci U S A. Jun 1; 118(22): e2026184118, 2021, doi: 10.1073/pnas.2026184118

URL
K e y w o r d Infectious disease, chronic hepatitis c, MHC class I