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AKT phosphorylation of hnRNPA1 modulates T cell fate and function

Award Number: F31AI152320
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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AKT phosphorylation of hnRNPA1 modulates T cell fate and function - AKT phosphorylation of hnRNPA1 and hnRNPL modulates T cell fate and function Regulatory T cells (Treg) play a significant role in maintaining self-tolerance and preventing autoimmune diseases. We and others have shown that low dose favors Treg and T helper (Th) 2 cell differentiation, while high Ag dose stimulation activates the PI3K/Akt/mTOR pathway, favoring inflammatory Th1 and Th17 cell differentiation (Teff). Differences in PI3K/Akt/mTOR signaling not only affect T cell fate but our research shows that Akt phosphorylation of the RNA-binding protein, (RBP) heterogeneous nuclear ribonucleoprotein (hnRNP) A1, is dependent on TCR signal strength. RBPs such as hnRNPA1 are emerging as regulators of RNA processing and stability in immune cells, and the effect of RBP on T cell differentiation is a growing subject of interest. We have shown hnRNPA1 is required for optimal Treg differentiation by performing knockdown experiments, and that it is phosphorylated by Akt following low dose stimulation. Our present research is focused on identifying a role for Akt phosphorylation in hnRNPA1 function. HnRNPA1 is known to have a single Akt phosphorylation site at S199 and our lab has generated a new mutant mouse model, hnRNPA1-S199A (mA1). This mutation affects the ability of Akt to phosphorylate hnRNPA1 in all immune cells. Preliminary data suggest that Treg differentiation induced by low TCR stimulation is impaired in the T cells from the mutant mouse. Based on these preliminary findings we hypothesize that Akt-mediated phosphorylation of hnRNPL and/or hnRNPA1 upon low TCR stimulation controls the processing of RNA transcripts involved in Treg differentiation. The following specific aims are proposed; 1) To determine how the hnRNPA1-S199A mutation affects T cell fate and function. 2) To determine the impact hnRNPA1 has on RNA splicing and stability. 3) To identify the AKT phosphorylation site on hnRNPL. 4)To determine how hnRNPL effects T cell fate and function.


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: 2023 ( Subtotal = -$44,151 )
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	002	3	6/20/2023	NON-COMPETING CONTINUATION	-$20,396
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	11/23/2022	NON-COMPETING CONTINUATION	-$16,105
2023	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	2	6/20/2023	NON-COMPETING CONTINUATION	-$7,650
														Subtotal = -$44,151

Issue Date FY: 2022 ( Subtotal = $36,501 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	7/12/2022	NON-COMPETING CONTINUATION	$36,501
														Subtotal = $36,501

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	7/21/2021	NON-COMPETING CONTINUATION	$46,036
														Subtotal = $46,036

Issue Date FY: 2020 ( Subtotal = $45,520 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	7/20/2020	NEW	$45,520
														Subtotal = $45,520

Grand Total All Awards = $83,906

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AKT phosphorylation of hnRNPA1 modulates T cell fate and function

Award Number: F31AI152320

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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