iRhom2 is essential for innate immunity to RNA virus by antagonizing ER- and mitochondria-associated degradation of VISA
| Autor: | Huan Lian, Pan Cao, Wei-Wei Luo, Zhou-Qin Zheng, Shu Li, Yan-Yi Wang, Chen Li, Hong-Bing Shu, Su-Yun Wang, Zhen Tong |
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| Rok vydání: | 2017 |
| Předmět: |
RNA viruses
0301 basic medicine Pathology and Laboratory Medicine Biochemistry Ligases RNA Virus Infections Ubiquitin Medicine and Health Sciences Enzyme-Linked Immunoassays Immune Response lcsh:QH301-705.5 biology Intracellular Signaling Peptides and Proteins Endoplasmic Reticulum-Associated Degradation Precipitation Techniques Enzymes Ubiquitin ligase DNA-Binding Proteins Immunoblot Analysis Vesicular Stomatitis Virus Medical Microbiology Vesicular stomatitis virus Viral Pathogens Viruses Pathogens Research Article lcsh:Immunologic diseases. Allergy Ubiquitin-Protein Ligases Immunology Molecular Probe Techniques Endoplasmic-reticulum-associated protein degradation Research and Analysis Methods Microbiology Rhabdoviruses 03 medical and health sciences Immune system Virology Genetics Humans Immunoprecipitation Molecular Biology Techniques Immunoassays Microbial Pathogens Molecular Biology MARCH5 Adaptor Proteins Signal Transducing Innate immune system Ubiquitination Organisms Biology and Life Sciences Proteins RNA virus biology.organism_classification Immunity Innate Co-Immunoprecipitation 030104 developmental biology lcsh:Biology (General) Proteolysis Immunologic Techniques Enzymology biology.protein Parasitology Carrier Proteins lcsh:RC581-607 Viral Transmission and Infection |
| Zdroj: | PLoS Pathogens, Vol 13, Iss 11, p e1006693 (2017) PLoS Pathogens |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1006693 |
| Popis: | VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms. In un-infected and early infected cells, iRhom2 mediates auto-ubiquitination and degradation of the E3 ubiquitin ligase RNF5 and impairs the assembly of VISA-RNF5-GP78 complexes, thereby antagonizes ER-associated degradation (ERAD) of VISA. In the late phase of viral infection, iRhom2 mediates proteasome-dependent degradation of the E3 ubiquitin ligase MARCH5 and impairs mitochondria-associated degradation (MAD) of VISA. Maintenance of VISA stability by iRhom2 ensures efficient innate antiviral response at the early phase of viral infection and ready for next round of response. Our findings suggest that iRhom2 acts as a checkpoint for the ERAD/MAD of VISA, which ensures proper innate immune response to RNA virus. Author summary VISA is a central adaptor in innate immune response to RNA virus, which is down-regulated by multiple ubiquitination-dependent mechanisms. In this study, we found that the ER-associated protein iRhom2 promotes VISA stability by suppressing ER- and mitochondria-associated degradation pathways in early- and late-infected cells respectively, thereby plays an essential role in efficient innate immune response to RNA virus. |
| Databáze: | OpenAIRE |
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