Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB

Janina Bruening; Lisa Lasswitz; Pia Banse; Sina Kahl; Carine Marinach; Florian W Vondran; Lars Kaderali; Olivier Silvie; Thomas Pietschmann; Felix Meissner; Gisa Gerold

doi:10.1371/journal.ppat.1007111

Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB

PLoS Pathog. 2018 Jul 19;14(7):e1007111. doi: 10.1371/journal.ppat.1007111. eCollection 2018 Jul.

Authors

Affiliations

¹ Insitute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
² Sorbonne Université, INSERM, CNRS, Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Paris, France.
³ Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
⁴ Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany.
⁵ Department of Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany.
⁶ Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden.
⁷ Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden.

Abstract

Hepatitis C virus (HCV) and the malaria parasite Plasmodium use the membrane protein CD81 to invade human liver cells. Here we mapped 33 host protein interactions of CD81 in primary human liver and hepatoma cells using high-resolution quantitative proteomics. In the CD81 protein network, we identified five proteins which are HCV entry factors or facilitators including epidermal growth factor receptor (EGFR). Notably, we discovered calpain-5 (CAPN5) and the ubiquitin ligase Casitas B-lineage lymphoma proto-oncogene B (CBLB) to form a complex with CD81 and support HCV entry. CAPN5 and CBLB were required for a post-binding and pre-replication step in the HCV life cycle. Knockout of CAPN5 and CBLB reduced susceptibility to all tested HCV genotypes, but not to other enveloped viruses such as vesicular stomatitis virus and human coronavirus. Furthermore, Plasmodium sporozoites relied on a distinct set of CD81 interaction partners for liver cell entry. Our findings reveal a comprehensive CD81 network in human liver cells and show that HCV and Plasmodium highjack selective CD81 interactions, including CAPN5 and CBLB for HCV, to invade cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Calpain / metabolism*
Cell Line
Hepacivirus / metabolism*
Hepatitis C / metabolism
Host-Pathogen Interactions / physiology*
Humans
Proto-Oncogene Mas
Proto-Oncogene Proteins c-cbl / metabolism*
Tetraspanin 28 / metabolism*
Virus Internalization*

Substances

Adaptor Proteins, Signal Transducing
CD81 protein, human
MAS1 protein, human
Proto-Oncogene Mas
Tetraspanin 28
CBLB protein, human
Proto-Oncogene Proteins c-cbl
Calpain
Capn5 protein, human

Grants and funding

This work was supported by a fellowship from the Hannover Biomedical Research School and the Centre for Infection Biology (ZIB, https://www.mh-hannover.de/zib_zib.html) to JB, grants from the Deutsche Forschungsgemeinschaft (SFB 900, project A6, www.sfb900.de) and the Helmholtz Association SO-024 to TP (www.helmholtz.de), grants from the European Union (FP7 PathCo Collaborative Project HEALTH-F3-2012-305578, www.pathco.org) and the Laboratoire d'Excellence ParaFrap (ANR-11-LABX-0024, www.labex-parafrap.fr) to OS, and grants from the Human Frontier Science Program (LT-000048-2009, www.hfsp.org/), the German Academy of Science Leopoldina (LPDS 2009-9, www.leopoldina.org), the Deutsche Forschungsgemeinschaft (DFG, GE 2145/3-1&2, http://gepris.dfg.de/gepris/projekt/246964086) and the Deutsche Leberstiftung (S163/10073/2011, www.deutsche-leberstiftung.de/) to GG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.