Correction: RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response
| العنوان: | Correction: RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response |
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| المؤلفون: | Peng Zhang, Ze Hong, Juanjuan Zhu, Jin-fu Xu, Haiyang Hu, Ye Cui, Huansha Yu, Dong Qian, Chenhui Li, Quanyi Wang, Chen Wang, Lele Zhang, Mingxing Cheng, Wei Meng, Yi Sun |
| المصدر: | PLoS Pathogens PLoS Pathogens, Vol 17, Iss 3, p e1009401 (2021) |
| بيانات النشر: | Public Library of Science, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Small interfering RNA, NEDD8, Biochemistry, Physical Chemistry, Mice, 0302 clinical medicine, Interferon, Medicine and Health Sciences, Biology (General), Enzyme-Linked Immunoassays, Post-Translational Modification, Phosphorylation, Immune Response, 0303 health sciences, biology, Chemistry, Nucleotidyltransferases, Cell biology, Ubiquitin ligase, Precipitation Techniques, Nucleic acids, Virus Diseases, 030220 oncology & carcinogenesis, Physical Sciences, Dimerization, Signal Transduction, medicine.drug, Research Article, QH301-705.5, Ubiquitin-Protein Ligases, Immunology, Research and Analysis Methods, Transfection, Microbiology, Proinflammatory cytokine, 03 medical and health sciences, Immune Deficiency, Immune system, Virology, medicine, Genetics, Animals, Humans, Immunoprecipitation, Molecular Biology Techniques, Non-coding RNA, Immunoassays, Molecular Biology, 030304 developmental biology, Innate immune system, Biology and life sciences, Correction, Proteins, RC581-607, Immunity, Innate, Gene regulation, Chemical Properties, Ubiquitin-Conjugating Enzymes, biology.protein, Immunologic Techniques, RNA, Parasitology, Clinical Immunology, Neddylation, Gene expression, Immunologic diseases. Allergy, Clinical Medicine, Protein Processing, Post-Translational |
| الوصف: | The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. By performing mass spectrometry, we identified Lys231 and Lys421 as essential neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense. Author summary The Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a critical cytosolic DNA sensor by monitoring pathogens-derived DNA, while its aberrant activation leads to tissue damage. Thus, the activity of cGAS must be tightly regulated to keep immune homeostasis. Several post-translational modifications have been demonstrated to be important in fine-tuning activities of cGAS. However, the mechanism underlying how cGAS is precisely regulated remains not fully understood. In this study, we uncovered that cGAS was poly-neddylated by the Ube2m-Rnf111 axis, and the poly-NEDD8 chains played a role as nexus in linking the second cGAS, leading to the appropriate dimerization and the subsequent activation of cGAS. Our study revealed a novel and critical role of neddylation in the regulation of the cGAS-STING signaling pathway and provided a new perspective for restricting the infection of DNA pathogens. |
| اللغة: | English |
| تدمد: | 1553-7374 1553-7366 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::77e6a950e4c316465b673dd95d5d4ef4Test http://europepmc.org/articles/PMC7959372Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....77e6a950e4c316465b673dd95d5d4ef4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537374 15537366 |
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