Correction: RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response

Autor: 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
Jazyk: angličtina
Rok vydání: 2021
Předmět:
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
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 17, Iss 3, p e1009401 (2021)
ISSN: 1553-7374
1553-7366
Popis: 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.
Databáze: OpenAIRE