Monday, June 30, 2025 6/30/2025

Molecular basis of viral DNA sensing through the cGAS-STING pathway

Award Number: R01AI145287
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/20/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Molecular basis of viral DNA sensing through the cGAS-STING pathway - The Molecular Basis of Viral DNA Sensing through the cGAS-STING Pathway The innate immune response is the first line of defense against bacterial or viral infections. Nucleic acids from the pathogens serve as danger signals to the host and induce potent innate immune responses. The cGAS- STING pathway plays a central role in sensing viral DNA. Upon DNA binding, cGAS is activated and catalyzes the synthesis of a second messenger cyclic-GMP-AMP (cGAMP). The engagement of cGAMP by STING initiates three lines of signaling events. First, the transcription factor IRF3 is activated and initiates the induction of type I interferon (IFN-I). Second, the transcription factor NF-kB is activated, which synergizes with IRF3 to promote the transcription of IFN-I genes and mediates the induction of proinflammatory cytokines. Third, the activation of STING induces noncanonical autophagy, which is also important for the clearance of intracellular pathogens. The molecular mechanism of the cGAS-STING pathway has been studied extensively over the last few years. The crystal structure of cGAS bound to dsDNA demonstrates that cGAS is activated by DNA induced oligomerization. The structures of STING bound to cGAMP and small molecule agonists reveal the mechanism of STING activation upon ligand binding. The crystal structures of TBK1 and IRF3 bound to peptides from STING C-terminal tail reveal the molecular bases of TBK1 and IRF3 recruitment and activation. The structures of phosphorylated IRF3 provide insight into the mechanism of IRF3 activation by TBK1. The cryo-EM structure of cGAS bound to the nucleosome core particle reveals the mechanism of cGAS inhibition under resting condition. These comprehensive structural and functional studies significantly advanced our understanding about the cGAS-STING pathway. Despite these extensive studies, many aspects of the cGAS- STING pathway remain poorly understood. As a diffusible second messenger, cGAMP can be exported from infected cells and imported by uninfected cells to induce the expression of IFNs. However, the structural basis of cGAMP export remains to be determined. The exact mechanism of IRF3 activation upon phosphorylation by TBK1 remains poorly defined. The activation of NF-kB plays a critical role in IFN-independent response mediated by STING. However, the mechanism of NF-kB activation via STING in remains to be determined. The proposed research will elucidate the molecular bases of several key events involved in the cGAS-STING pathway with the following aims: 1). Elucidate the structural basis of cGAMP export by ABCC1; 2). Determine the molecular basis of IRF3 activation upon phosphorylation; 3). Investigate the mechanism of NF-kB activation via STING. The proposed studies represent a rigorous and comprehensive investigation into the mechanisms of DNA sensing through the cGAS-STING pathway. It will dramatically advance our understanding of the molecular basis of innate immunity against viral DNA and provide a foundation for innovative approaches to treat viral disease, autoimmune disorder, and cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $360,883 )
2025	2025	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	6	1/22/2025	COMPETING CONTINUATION	$360,883
2025	2025	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	003	6	6/10/2025	COMPETING CONTINUATION	$14,651
2025	2023	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	002	5	6/10/2025	NON-COMPETING CONTINUATION	-$14,651
2025	2023	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	5	1/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $360,883

Issue Date FY: 2023 ( Subtotal = $360,879 )
2023	2023	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	5	1/3/2023	NON-COMPETING CONTINUATION	$360,879
														Subtotal = $360,879

Issue Date FY: 2022 ( Subtotal = $361,373 )
2022	2022	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	4	1/12/2022	NON-COMPETING CONTINUATION	$361,373
														Subtotal = $361,373

Issue Date FY: 2021 ( Subtotal = $361,843 )
2021	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	3	3/16/2021	NON-COMPETING CONTINUATION	$0
2021	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	3	1/28/2021	NON-COMPETING CONTINUATION	$361,843
														Subtotal = $361,843

Issue Date FY: 2020 ( Subtotal = $362,292 )
2020	2020	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	2	1/23/2020	NON-COMPETING CONTINUATION	$362,292
														Subtotal = $362,292

Issue Date FY: 2019 ( Subtotal = $362,718 )
2019	2019	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	1	7/2/2019	NEW	$0
2019	2019	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	1	2/18/2019	NEW	$362,718
														Subtotal = $362,718

Grand Total All Awards = $2,169,988

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Molecular basis of viral DNA sensing through the cGAS-STING pathway

Award Number: R01AI145287

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/20/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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