Enterovirus pathogenesis requires the host methyltransferase SETD3
| Autor: | Or Gozani, Jan E. Carette, Jeffrey R. Johnson, Peter Sarnow, Erik Verschueren, Jonathan Diep, Harry B. Greenberg, Tracy Young, Eileen Foy, Kristi J. Kobluk, James Zengel, Raul Andino, Christine E. Peters, Kuo-Feng Weng, Jiewei Xu, Alex W. Wilkinson, Ruth Hüttenhain, Siyuan Ding, Nevan J. Krogan, Gwendolyn M. Jang, Joshua E. Elias, Yaw Shin Ooi, Orly Laufman, Claude M. Nagamine |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
viruses
Viral pathogenesis medicine.disease_cause Virus Replication Applied Microbiology and Biotechnology Mice CRISPR 2.1 Biological and endogenous factors 2.2 Factors relating to the physical environment Encephalitis Viral Viral Aetiology Enterovirus 0303 health sciences Neuromuscular Diseases Myelitis 3. Good health Infectious Diseases Medical Microbiology Histone Methyltransferases Encephalitis Infection Microbiology (medical) Immunology Biology Microbiology Article 03 medical and health sciences Viral Proteins Viral life cycle medicine Enterovirus Infections Genetics Animals 030304 developmental biology 030306 microbiology Animal Viral encephalitis RNA Cell Biology Methyltransferases medicine.disease Virology Acute flaccid myelitis Disease Models Animal Good Health and Well Being Viral replication Disease Models Proteolysis Central Nervous System Viral Diseases CRISPR-Cas Systems |
| Zdroj: | Nature microbiology, vol 4, iss 12 Nature microbiology |
| Popis: | Enteroviruses (EVs) comprise a large genus of positive-sense, single-stranded RNA viruses whose members cause a number of important and widespread human diseases, including poliomyelitis, myocarditis, acute flaccid myelitis and the common cold. How EVs co-opt cellular functions to promote replication and spread is incompletely understood. Here, using genome-scale CRISPR screens, we identify the actin histidine methyltransferase SET domain containing 3 (SETD3) as critically important for viral infection by a broad panel of EVs, including rhinoviruses and non-polio EVs increasingly linked to severe neurological disease such as acute flaccid myelitis (EV-D68) and viral encephalitis (EV-A71). We show that cytosolic SETD3, independent of its methylation activity, is required for the RNA replication step in the viral life cycle. Using quantitative affinity purification-mass spectrometry, we show that SETD3 specifically interacts with the viral 2A protease of multiple enteroviral species, and we map the residues in 2A that mediate this interaction. 2A mutants that retain protease activity but are unable to interact with SETD3 are severely compromised in RNA replication. These data suggest a role of the viral 2A protein in RNA replication beyond facilitating proteolytic cleavage. Finally, we show that SETD3 is essential for in vivo replication and pathogenesis in multiple mouse models for EV infection, including CV-A10, EV-A71 and EV-D68. Our results reveal a crucial role of a host protein in viral pathogenesis, and suggest targeting SETD3 as a potential mechanism for controlling viral infections. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|