Affiliation:
1. Institutes of Biology and Medical Sciences MOE Key Laboratory of Geriatric Diseases and Immunology Jiangsu Key Laboratory of Infection and Immunity Soochow University Suzhou 215000 China
2. Department of Clinical Laboratory The Affiliated Suzhou Hospital of Nanjing Medical University Suzhou Municipal Hospital Gusu School of Nanjing Medical University Suzhou 215000 China
3. School of Biology and Basic Medical Science Suzhou Medical College of Soochow University Suzhou 215000 China
4. Shanghai‐MOST Key Laboratory of Health and Disease Genomics NHC Key Lab of Reproduction Regulation Shanghai Institute for Biomedical and Pharmaceutical Technologies Shanghai 200000 China
5. National Key Laboratory of Immunity and Inflammation and CAMS Key Laboratory of Synthetic Biology Regulatory Elements Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences & Peking Union Medical College Suzhou 215123 China
Abstract
AbstractArboviruses, transmitted by medical arthropods, pose a serious health threat worldwide. During viral infection, Post Translational Modifications (PTMs) are present on both host and viral proteins, regulating multiple processes of the viral lifecycle. In this study, a mammalian E3 ubiquitin ligase WWP2 (WW domain containing E3 ubiquitin ligase 2) is identified, which interacts with the NS1 protein of Zika virus (ZIKV) and mediates K63 and K48 ubiquitination of Lys 265 and Lys 284, respectively. WWP2‐mediated NS1 ubiquitination leads to NS1 degradation via the ubiquitin‐proteasome pathway, thereby inhibiting ZIKV infection in mammalian hosts. Simultaneously, it is found Su(dx), a protein highly homologous to host WWP2 in mosquitoes, is capable of ubiquitinating NS1 in mosquito cells. Unexpectedly, ubiquitination of NS1 in mosquitoes does not lead to NS1 degradation; instead, it promotes viral infection in mosquitoes. Correspondingly, the NS1 K265R mutant virus is less infectious to mosquitoes than the wild‐type (WT) virus. The above results suggest that the ubiquitination of the NS1 protein confers different adaptations of ZIKV to hosts and vectors, and more importantly, this explains why NS1 K265‐type strains have become predominantly endemic in nature. This study highlights the potential application in antiviral drug and vaccine development by targeting viral proteins' PTMs.
Funder
Priority Academic Program Development of Jiangsu Higher Education Institutions
National Natural Science Foundation of China
Natural Science Foundation of Jiangsu Province