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• W3136148592 startingPage "e1009401" @default.
• W3136148592 abstract "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." @default.
• W3136148592 created "2021-03-29" @default.
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• W3136148592 date "2021-03-15" @default.
• W3136148592 modified "2023-10-15" @default.
• W3136148592 title "RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response" @default.
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• W3136148592 doi "https://doi.org/10.1371/journal.ppat.1009401" @default.
• W3136148592 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7959372" @default.
• W3136148592 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33720974" @default.
• W3136148592 hasPublicationYear "2021" @default.
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