Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis
Summary: The monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5-mediated antiviral signaling. In quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFN-α/β) production and autoimmun...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220302443 |
| _version_ | 1818516490306977792 |
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| author | Yuheng Shi Jing Wu Tiansheng Zhong Wenting Zhu Guolan She Hao Tang Wei Du Bang-Ce Ye Nan Qi |
| author_facet | Yuheng Shi Jing Wu Tiansheng Zhong Wenting Zhu Guolan She Hao Tang Wei Du Bang-Ce Ye Nan Qi |
| author_sort | Yuheng Shi |
| collection | DOAJ |
| description | Summary: The monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5-mediated antiviral signaling. In quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFN-α/β) production and autoimmune diseases like systemic lupus erythematosus. However, the detailed mechanism by which MAVS is kept from spontaneous aggregation remains largely unclear. Here, we show that upstream open reading frames (uORFs) within the MAVS transcripts exert a post-transcriptional regulation for preventing MAVS spontaneous aggregation and auto-activation. Mechanistically, we demonstrate that uORFs are cis-acting elements initiating leaky ribosome scanning of the downstream ORF codons, thereby repressing the full-length MAVS translation. We further uncover that endogenous MAVS generated from the uORF-deprived transcript spontaneously aggregates, triggering the Nix-mediated mitophagic clearance of damaged mitochondria and aggregated MAVS. Our findings reveal the uORF-mediated quantity and quality control of MAVS, which prevents aberrant protein aggregation and maintains innate immune homeostasis. |
| first_indexed | 2024-12-11T00:42:58Z |
| format | Article |
| id | doaj.art-39bf4b457bc8480e9eef82037e4c115e |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-11T00:42:58Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-39bf4b457bc8480e9eef82037e4c115e2022-12-22T01:26:51ZengElsevieriScience2589-00422020-05-01235Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune HomeostasisYuheng Shi0Jing Wu1Tiansheng Zhong2Wenting Zhu3Guolan She4Hao Tang5Wei Du6Bang-Ce Ye7Nan Qi8Institute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 20032, ChinaInstitute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, ChinaInstitute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, ChinaMaterials Interfaces Center Institute of Advanced Materials Science and Engineering Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, ChinaInstitute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, ChinaInstitute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, ChinaInstitute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, ChinaInstitute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, ChinaInstitute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China; Corresponding authorSummary: The monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5-mediated antiviral signaling. In quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFN-α/β) production and autoimmune diseases like systemic lupus erythematosus. However, the detailed mechanism by which MAVS is kept from spontaneous aggregation remains largely unclear. Here, we show that upstream open reading frames (uORFs) within the MAVS transcripts exert a post-transcriptional regulation for preventing MAVS spontaneous aggregation and auto-activation. Mechanistically, we demonstrate that uORFs are cis-acting elements initiating leaky ribosome scanning of the downstream ORF codons, thereby repressing the full-length MAVS translation. We further uncover that endogenous MAVS generated from the uORF-deprived transcript spontaneously aggregates, triggering the Nix-mediated mitophagic clearance of damaged mitochondria and aggregated MAVS. Our findings reveal the uORF-mediated quantity and quality control of MAVS, which prevents aberrant protein aggregation and maintains innate immune homeostasis.http://www.sciencedirect.com/science/article/pii/S2589004220302443Biological SciencesCell BiologyImmunologyMolecular Biology |
| spellingShingle | Yuheng Shi Jing Wu Tiansheng Zhong Wenting Zhu Guolan She Hao Tang Wei Du Bang-Ce Ye Nan Qi Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis iScience Biological Sciences Cell Biology Immunology Molecular Biology |
| title | Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis |
| title_full | Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis |
| title_fullStr | Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis |
| title_full_unstemmed | Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis |
| title_short | Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis |
| title_sort | upstream orfs prevent mavs spontaneous aggregation and regulate innate immune homeostasis |
| topic | Biological Sciences Cell Biology Immunology Molecular Biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220302443 |
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