Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway
Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA imm...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715010189 |
| _version_ | 1828389582613250048 |
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| author | Gil Ju Seo Aerin Yang Brandon Tan Sungyoon Kim Qiming Liang Younho Choi Weiming Yuan Pinghui Feng Hee-Sung Park Jae U. Jung |
| author_facet | Gil Ju Seo Aerin Yang Brandon Tan Sungyoon Kim Qiming Liang Younho Choi Weiming Yuan Pinghui Feng Hee-Sung Park Jae U. Jung |
| author_sort | Gil Ju Seo |
| collection | DOAJ |
| description | Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts’ immune responses to DNA stimulation. |
| first_indexed | 2024-12-10T06:32:38Z |
| format | Article |
| id | doaj.art-5ad96c106b164e789af7f50e5f286e64 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T06:32:38Z |
| publishDate | 2015-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-5ad96c106b164e789af7f50e5f286e642022-12-22T01:59:02ZengElsevierCell Reports2211-12472015-10-0113244044910.1016/j.celrep.2015.09.007Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing PathwayGil Ju Seo0Aerin Yang1Brandon Tan2Sungyoon Kim3Qiming Liang4Younho Choi5Weiming Yuan6Pinghui Feng7Hee-Sung Park8Jae U. Jung9Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADepartment of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of KoreaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADepartment of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of KoreaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADepartment of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of KoreaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USAUpon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts’ immune responses to DNA stimulation.http://www.sciencedirect.com/science/article/pii/S2211124715010189 |
| spellingShingle | Gil Ju Seo Aerin Yang Brandon Tan Sungyoon Kim Qiming Liang Younho Choi Weiming Yuan Pinghui Feng Hee-Sung Park Jae U. Jung Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway Cell Reports |
| title | Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway |
| title_full | Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway |
| title_fullStr | Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway |
| title_full_unstemmed | Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway |
| title_short | Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway |
| title_sort | akt kinase mediated checkpoint of cgas dna sensing pathway |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715010189 |
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