Human MARCH1, 2, and 8 Block Ebola Virus Envelope Glycoprotein Cleavage via Targeting Furin P Domain
Changqing Yu 1 #, Wenbo Tan 4#, Yu Bai 5#, Yulong Zhou 8, Jingbo Zhai 6, Mengzhou Xue 7, Chunfu Zheng 2,9*, Qiang Liu 3*
1 Egineering Center of Agricultural Biosafety Assessment and Biotechnology, School of Advanced Agricultural Sciences, Yibin Vocational and Technical College, Yibin, People’s Republic of China;
2 Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Key Laboratory of Livestock Disease Prevention of Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, People’s Republic of China;
3 Nanchong Key Laboratory of Disease Prevention, Control and Detection in Livestock and Poultry, Nanchong Vocational and Technical College, Nanchong, People’s Republic of China;
4 College of Advanced Agriculture and Ecological Environment, Heilongjiang University, Harbin, People’s Republic of China;
5 College of Animal Science, Wenzhou Vocational College of Science and Technology, Wenzhou, People’s Republic of China;
6 Key Laboratory of Zoonose Prevention and Control at Universities of Inner Mongolia Autonomous Region, Medical College, Inner Mongolia Minzu University, Tongliao, People’s Republic of China;
7 Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, 2 Jingba Road, Zhengzhou, Henan, People’s Republic of China;
8 College of Animal Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, People’s Republic of China;
9 Department of Microbiology, Immunology & Infection Diseases, University of Calgary, Calgary, Alberta, Canada.
# These authors contributed equally to this work.
* Correspondence
Chunfu Zheng, zheng.alan@hotmail.com
Qiang Liu, liuqiang_yyy@163.com
Abstract: Membrane-Associated Ring-CH (MARCH) family proteins were recently reported to inhibit viral replication through multiple modes of action. Previous work proved that human MARCH8 blocked Ebola virus (EBOV) glycoprotein (GP) maturation. Our study here demonstrates that human MARCH1 and MARCH2 share a similar pattern to MARCH8 in restricting EBOV GP-mediated viral replication. Human MARCH1 and MARCH2 retain EBOV GP in the trans-Golgi network (TGN), reduce its surface display, and impair EBOV GP-pseudotyped virions infectivity. Furthermore, we uncover that the host proprotein convertase (PC) furin could interact with human MARCH1/2 and EBOV GP intracellularly. Importantly, the furin P domain is confirmed to be recognized by MARCH1/2/8, which is critical for their blocking activities. Besides, bovine MARCH2 and murine MARCH1 also impair EBOV GP proteolytic processing. Altogether, our findings confirm that MARCH1/2 proteins of different species showed a relatively conserved feature in blocking EBOV GP proteolytic processing, which could provide a reference for subsequent antiviral studies and may facilitate the development of novel strategies to antagonize enveloped virus infection.