RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.

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 r...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Chenhui Li, Lele Zhang, Dong Qian, Mingxing Cheng, Haiyang Hu, Ze Hong, Ye Cui, Huansha Yu, Quanyi Wang, Juanjuan Zhu, Wei Meng, Jin-Fu Xu, Yi Sun, Peng Zhang, Chen Wang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/95401f6be3be41ad98586ad3bb65d14b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:95401f6be3be41ad98586ad3bb65d14b
record_format	dspace
spelling	oai:doaj.org-article:95401f6be3be41ad98586ad3bb65d14b2021-12-02T19:59:37ZRNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.1553-73661553-737410.1371/journal.ppat.1009401https://doaj.org/article/95401f6be3be41ad98586ad3bb65d14b2021-03-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009401https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The 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.Chenhui LiLele ZhangDong QianMingxing ChengHaiyang HuZe HongYe CuiHuansha YuQuanyi WangJuanjuan ZhuWei MengJin-Fu XuYi SunPeng ZhangChen WangPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 3, p e1009401 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Chenhui Li Lele Zhang Dong Qian Mingxing Cheng Haiyang Hu Ze Hong Ye Cui Huansha Yu Quanyi Wang Juanjuan Zhu Wei Meng Jin-Fu Xu Yi Sun Peng Zhang Chen Wang RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.
description	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.
format	article
author	Chenhui Li Lele Zhang Dong Qian Mingxing Cheng Haiyang Hu Ze Hong Ye Cui Huansha Yu Quanyi Wang Juanjuan Zhu Wei Meng Jin-Fu Xu Yi Sun Peng Zhang Chen Wang
author_facet	Chenhui Li Lele Zhang Dong Qian Mingxing Cheng Haiyang Hu Ze Hong Ye Cui Huansha Yu Quanyi Wang Juanjuan Zhu Wei Meng Jin-Fu Xu Yi Sun Peng Zhang Chen Wang
author_sort	Chenhui Li
title	RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.
title_short	RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.
title_full	RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.
title_fullStr	RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.
title_full_unstemmed	RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.
title_sort	rnf111-facilitated neddylation potentiates cgas-mediated antiviral innate immune response.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/95401f6be3be41ad98586ad3bb65d14b
work_keys_str_mv	AT chenhuili rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT lelezhang rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT dongqian rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT mingxingcheng rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT haiyanghu rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT zehong rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT yecui rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT huanshayu rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT quanyiwang rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT juanjuanzhu rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT weimeng rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT jinfuxu rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT yisun rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT pengzhang rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse AT chenwang rnf111facilitatedneddylationpotentiatescgasmediatedantiviralinnateimmuneresponse
_version_	1718375738495729664

RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.

Ejemplares similares