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Determining the impact of post-translational modification on Serine Arginine Splicing Factor 7 during macrophage activation

Award Number: F31GM143893
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 12/14/2023

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Determining the impact of post-translational modification on Serine Arginine Splicing Factor 7 during macrophage activation - Project Summary There is a fundamental gap in our understanding of how RNA processing factors, specifically splicing proteins, respond to environmental changes and extracellular signals. The overall objective of this proposal is to define how the splicing factor SRSF7 is post-translationally modified and functionally altered in innate immune cells following activation by pathogen sensing. Misregulation of splicing accounts for a multitude of human diseases due to hereditary and somatic mutations in both cis and trans factors. Trans-acting splicing factors include aux- iliary splicing factors such as the Serine Arginine Splicing Factor (SRSF) family, and a recent phosphoproteomics experiment demonstrated that five SRSF proteins are differentially phosphorylated in primary macrophages in- fected with an intracellular bacterial pathogen. Upon stimulation of a macrophage cell line with lipopolysaccharide (LPS), one differentially phosphorylated SRSF protein, SRSF7, moves from the chromatin fraction to the nucle- oplasm and this movement is associated with an apparent gain in phosphorylation. This finding suggests that pathogen sensing may alter the ability of SRSF7 to interact with protein binding partners and/or RNA on chro- matin. Follow-up mass spec immunoprecipitation (MS-IP) of FLAG-SRSF7 in resting macrophages identified novel interactions between SRSF7 and SNRP70, a component of the U1 SNRP, and HDAC6 an important his- tone deacetylase. Additional preliminary data show that shRNA-mediated knockdown of SRSF7 represses levels of interferon stimulated genes (ISGs) in macrophages, suggesting this factor plays an important role in regulating innate immune gene expression. The central hypothesis of this proposal predicts that differential phosphory- lation of SRSF7 impacts its ability to bind proteins and pre-mRNA, which changes how the splicing code is read during macrophage activation. The two main goals of this project are to determine the contribution of phosphorylation of SRSF7 to protein-protein interactions and splicing during macrophage activation and to iden- tify the kinases involved in SRSF7 modification downstream of macrophage activation. To these ends, Aim1 uses immunoprecipitation to elucidate protein-protein interactions as well as RNA immunoprecipitation and RNA affinity assays to link SRSF7 phosphorylation status with protein/transcript binding and gene expression out- comes. Aim 2 employs biochemical inhibitors as well as genetic manipulation to determine the contribution of specific serine-threonine kinases in phosphorylation of SRSF7 during macrophage activation. These experi- ments will provide valuable insight into the activity and regulation of SRSF7 phosphorylation during macrophage activation. Additionally, this project will further our understanding of the mechanisms driving cellular adaptation to dynamic microenvironments. This work has high potential to shift paradigms regarding how a variety of envi- ronmental stresses (e.g. starvation, UV stress, heat shock, osmotic stress, carcinogenesis) functionalize RNA processing machinery and provides potential advancements for possible therapeutic interventions that correct disruption of cellular homeostasis by modulating pre-mRNA splicing.


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 = -$5,336 )
2025	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	3	10/23/2024	NON-COMPETING CONTINUATION	-$5,336
														Subtotal = -$5,336

Issue Date FY: 2024 ( Subtotal = -$19,349 )
2024	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	3	5/9/2024	NON-COMPETING CONTINUATION	-$19,349
														Subtotal = -$19,349

Issue Date FY: 2023 ( Subtotal = $36,201 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	3	7/12/2023	NON-COMPETING CONTINUATION	$36,201
														Subtotal = $36,201

Issue Date FY: 2022 ( Subtotal = $35,259 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	000	2	7/14/2022	NON-COMPETING CONTINUATION	$35,259
														Subtotal = $35,259

Issue Date FY: 2021 ( Subtotal = $34,543 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	001	1	7/22/2021	NEW	$0
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	000	1	7/22/2021	NEW	$34,543
														Subtotal = $34,543

Grand Total All Awards = $81,318

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Determining the impact of post-translational modification on Serine Arginine Splicing Factor 7 during macrophage activation

Award Number: F31GM143893

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 12/14/2023

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