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TRIM 14 is a master regulator of STAT3 activity during the macrophage innate immune responses to Mycobacterium tuberculosis

Award Number: F31AI176795
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY There is a fundamental gap in our knowledge of how mitochondria homeostasis contributes to immune re- sponses to infectious pathogens. The overall objective of this proposal is to define how the tripartite motif con- taining protein TRIM14 regulates STAT3 activity to modulate mitochondria health and innate immune outcomes during Mycobacterium tuberculosis (Mtb) infection. Recent studies have shown that TRIM14 negatively regulates type I IFN responses during Mtb infection through interactions with the cytosolic DNA sensing kinase TBK1 and the transcription factor STAT3. Specifically, TRIM14 was shown to be required for TBK1 phosphorylation of STAT3 at S727, which controls STAT3’s ability to translocate to the nucleus and turn on expression of negative regulators of IFNAR to dampen type I IFN responses. Interestingly, additional studies of Trim14-/- macrophages demonstrated several mitochondrial-related defects, including altered metabolic profiles during Mtb infection and a propensity to undergo intrinsic apoptosis. STAT3 is a classical transcription factor, but recent studies have highlighted its role in mitochondrial respiration, generation of reactive oxygen species, and maintaining mito- chondrial membrane potential. These connections prompted interest into how this novel TRIM14-TBK1-STAT3 axis influences mitochondrial health and how disruption of this pathway impacts innate immune responses to the intracellular bacterial pathogen Mycobacterium tuberculosis. This proposal is designed to test the hypothesis that TRIM14 is a critical player in maintaining the integrity of the mitochondrial network by directing TBK1 phos- phorylation of STAT3 and promoting STAT3 accumulation in the mitochondrial matrix. Aim 1 of this proposal will define how TRIM14 alters TBK1’s ability to phosphorylate STAT3 and how STAT3 phosphorylation alters its subcellular localization. Aim 2 will investigate how TRIM14 and STAT3 control mitochondria depolarization and apoptosis during Mtb infection. Aim 3 will investigate how TRIM14’s regulation of mitochondria metabolism, apoptosis, and changes to innate immune cell populations alter the outcome of Mtb infection in a mouse model of disease. This work will further fundamental understanding of how the TRIM14-TBK1-STAT3 axis regulates mitochondria health, which may inform novel therapeutic interventions that could help control Mtb and improve tuberculosis patient outcomes.


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 = $37,797 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	2	1/22/2025	NON-COMPETING CONTINUATION	$37,797
2025	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	1	11/29/2024	NEW	$0
														Subtotal = $37,797

Issue Date FY: 2024 ( Subtotal = $37,652 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	1	11/28/2023	NEW	$36,372
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	1	5/13/2024	NEW	$1,280
														Subtotal = $37,652

Grand Total All Awards = $75,449

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TRIM 14 is a master regulator of STAT3 activity during the macrophage innate immune responses to Mycobacterium tuberculosis

Award Number: F31AI176795

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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