RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response
Authors: Chenhui Li
Ye Cui
Ze Hong
Peng Zhang
Wei Meng
Chen Wang
Lele Zhang
Juanjuan Zhu
Jin-Fu Xu
Huansha Yu
Haiyang Hu
Quanyi Wang
Mingxing Cheng
Dong Qian
Yi Sun
Journal: PLoS Pathogens (2021)
Discipline: MICROBIOLOGY
Keywords: cGAS; neddylation; STING; immune response; interferon
Affiliations: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China., Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China., Division of Immunology, The Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America., Cancer Institute of the 2nd affiliated hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

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. 

Retracted: No

PubPeer comments:
 In Figure 4A of the work, the photographs for Mock and ISD samples with DAPI are exactly the same. ![file] ![file] , 
 #1 I am Chenhui Li, the first author of this paper. During the preparation of figures for publication, we mistakenly pasted the panels of DAPI columns of Fig 4A twice to illustrate the nuclear DNAs of MEF cells between ISD stimulation and Mock controls. We have noticed this mistake before, the correction requirement has been sent to PLoS Pathogens including the original pictures and repeated experiment results. This mistake did not alter any conclusion and scientific integrity. Currently, the correction has been handled with the editor, and the formal erratum would be published soon. We apologize for this mistake for any inconvenience. The attached figure is the corrected Fig 4A with original panel pictures. ![file] ,