NEMO–IKKβ Are Essential for IRF3 and NF-κB Activation in the cGAS–STING Pathway
Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of many critical proteins, including NEMO, IKKβ, and TBK1, in this pathway are unclear because of the lack of an appropriate system to study. In...
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| Published in | The Journal of immunology (1950) Vol. 199; no. 9; pp. 3222 - 3233 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Association of Immunologists
01.11.2017
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of many critical proteins, including NEMO, IKKβ, and TBK1, in this pathway are unclear because of the lack of an appropriate system to study. In this article, we report that lower FBS concentrations in culture medium conferred high sensitivities to dsDNA in otherwise unresponsive cells, whereas higher FBS levels abrogated this sensitivity. Based on this finding, we demonstrated genetically that NEMO was critically involved in the cGAS–STING pathway. Cytosolic DNA activated TRIM32 and TRIM56 to synthesize ubiquitin chains that bound NEMO and subsequently activated IKKβ. Activated IKKβ, but not IKKα, was required for TBK1 and NF-κB activation. In contrast, TBK1 was reciprocally required for NF-κB activation, probably by directly phosphorylating IKKβ. Thus, our findings identified a unique innate immune activation cascade in which TBK1–IKKβ formed a positive feedback loop to assure robust cytokine production during cGAS–STING activation. |
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| AbstractList | Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of many critical proteins, including NEMO, IKKβ, and TBK1, in this pathway are unclear because of the lack of an appropriate system to study. In this article, we report that lower FBS concentrations in culture medium conferred high sensitivities to dsDNA in otherwise unresponsive cells, whereas higher FBS levels abrogated this sensitivity. Based on this finding, we demonstrated genetically that NEMO was critically involved in the cGAS–STING pathway. Cytosolic DNA activated TRIM32 and TRIM56 to synthesize ubiquitin chains that bound NEMO and subsequently activated IKKβ. Activated IKKβ, but not IKKα, was required for TBK1 and NF-κB activation. In contrast, TBK1 was reciprocally required for NF-κB activation, probably by directly phosphorylating IKKβ. Thus, our findings identified a unique innate immune activation cascade in which TBK1–IKKβ formed a positive feedback loop to assure robust cytokine production during cGAS–STING activation. Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of many critical proteins, including NEMO, IKKβ, and TBK1, in this pathway are unclear because of the lack of an appropriate system to study. In this article, we report that lower FBS concentrations in culture medium conferred high sensitivities to dsDNA in otherwise unresponsive cells, whereas higher FBS levels abrogated this sensitivity. Based on this finding, we demonstrated genetically that NEMO was critically involved in the cGAS-STING pathway. Cytosolic DNA activated TRIM32 and TRIM56 to synthesize ubiquitin chains that bound NEMO and subsequently activated IKKβ. Activated IKKβ, but not IKKα, was required for TBK1 and NF-κB activation. In contrast, TBK1 was reciprocally required for NF-κB activation, probably by directly phosphorylating IKKβ. Thus, our findings identified a unique innate immune activation cascade in which TBK1-IKKβ formed a positive feedback loop to assure robust cytokine production during cGAS-STING activation.Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of many critical proteins, including NEMO, IKKβ, and TBK1, in this pathway are unclear because of the lack of an appropriate system to study. In this article, we report that lower FBS concentrations in culture medium conferred high sensitivities to dsDNA in otherwise unresponsive cells, whereas higher FBS levels abrogated this sensitivity. Based on this finding, we demonstrated genetically that NEMO was critically involved in the cGAS-STING pathway. Cytosolic DNA activated TRIM32 and TRIM56 to synthesize ubiquitin chains that bound NEMO and subsequently activated IKKβ. Activated IKKβ, but not IKKα, was required for TBK1 and NF-κB activation. In contrast, TBK1 was reciprocally required for NF-κB activation, probably by directly phosphorylating IKKβ. Thus, our findings identified a unique innate immune activation cascade in which TBK1-IKKβ formed a positive feedback loop to assure robust cytokine production during cGAS-STING activation. |
| Author | Lv, Mengze Yu, Xiaoyu Bi, Sheng Gao, Pengfei Fang, Run Wang, Chenguang Zhang, Rui Feng, Ji-Ming Jiang, Zhengfan Jiang, Qifei Mu, Ping |
| Author_xml | – sequence: 1 givenname: Run surname: Fang fullname: Fang, Run – sequence: 2 givenname: Chenguang orcidid: 0000-0003-3464-4923 surname: Wang fullname: Wang, Chenguang – sequence: 3 givenname: Qifei surname: Jiang fullname: Jiang, Qifei – sequence: 4 givenname: Mengze orcidid: 0000-0002-8509-7969 surname: Lv fullname: Lv, Mengze – sequence: 5 givenname: Pengfei surname: Gao fullname: Gao, Pengfei – sequence: 6 givenname: Xiaoyu surname: Yu fullname: Yu, Xiaoyu – sequence: 7 givenname: Ping surname: Mu fullname: Mu, Ping – sequence: 8 givenname: Rui surname: Zhang fullname: Zhang, Rui – sequence: 9 givenname: Sheng surname: Bi fullname: Bi, Sheng – sequence: 10 givenname: Ji-Ming orcidid: 0000-0001-7956-2126 surname: Feng fullname: Feng, Ji-Ming – sequence: 11 givenname: Zhengfan surname: Jiang fullname: Jiang, Zhengfan |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28939760$$D View this record in MEDLINE/PubMed |
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| Snippet | Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of... Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of... |
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| Title | NEMO–IKKβ Are Essential for IRF3 and NF-κB Activation in the cGAS–STING Pathway |
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