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Transcript-selective translational control of Th17 cell development and function

Award Number: R21AI154039
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: 09/27/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Transcript-selective translational control of Th17 cell development and function - Project Summary Differentiation of naïve CD4+ T helper (TH) cells into effector or regulatory subsets determines whether an immune response is protective, ineffective or pathogenic. Through a standing collaboration with Dr. Malcolm Whitman, we have shown that the febrifugine family of plant natural products—including the synthetic derivative halofuginone (HF)—potently and selectively blocks human and mouse Th17 cell differentiation by activating a conserved stress response pathway, called the amino acid response (AAR). We further showed that HF activates the AAR by binding to the catalytic domain of the mammalian prolyl-tRNA synthetase, EPRS, and inhibiting prolyl-tRNA aminoacylation (i.e., charging). Uncharged tRNAs accumulate in cells during periods of amino acid restriction, and signal sequential translational and transcriptional responses via the ribosome- associated protein kinase, Gcn2, to reduce amino acid demand, increase amino acid supply and facilitate a return to homeostasis. Although HF-mediated EPRS inhibition induces rapid accumulation of uncharged prolyl- tRNAs and Gcn2 activation, we have shown that HF-mediated EPRS inhibition acts independent of known amino acid sensing pathways, including Gcn2, to repress both IL-6-driven Th17 cell differentiation and IL-23- induced ‘pathogenic’ Th17 cell function by selectively repressing Stat3 protein synthesis (i.e., translation). This proposal interrogates two pathways that we hypothesize underlie HF/EPRS-mediated Stat3 translational silencing. First, EPRS (the cellular receptor for HF) has an auxiliary, or ‘moonlighting’, function as the RNA- binding sub-unit of a transcript-selective translational regulatory complex, called GAIT (gamma interferon- activated inhibitor of translation). Assembled GAIT complexes bind and repress translation of select sets of inflammation-associated transcripts containing structurally conserved stem-loop motifs in their 3’ untranslated regions (UTRs), but has yet to be formally evaluated in TH cells. Second, we have shown that both HF- mediated AAR activation (Gcn2-dependent) and HF-dependent anti-inflammatory reprogramming (Gcn2- independent) in stromal cells requires another ribosome-associated protein, Gcn1. Although Gcn1 is known only for enhancing Gcn2-binding to uncharged tRNAs, our data suggest that Gcn1 can be functionally uncoupled from Gcn2, and may serve as a branch point from the canonical AAR pathway in cells responding to amino acid stress. To elucidate the contribution of these pathways to cellular responses to amino acid deprivation, and with an eye towards engineering new drug-like small molecules that retain Stat3 translational silencing activity without inhibiting an essential enzyme (EPRS), we will: (i) employ EPRS immunoprecipitation experiments to assess HF-driven GAIT complex assembly and Stat3 mRNA-binding in developing Th17 cells; and (ii) use inducible RNAi coupled with Ribo-tag mice to determine if HF/EPRS-mediated Stat3 translational repression requires Gcn1.Together, these studies will reveal novel insights into the translational regulation of TH cell differentiation, and inform new, more selective approaches to treat Th17-driven immune pathologies.


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: 2024 ( Subtotal = $0 )
2024	2023	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	003	4	1/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	004	4	8/19/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	002	4	12/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$123,438
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	3	12/11/2023	NON-COMPETING CONTINUATION	-$40,000
2024	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	2	12/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$83,438
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2023	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	002	4	2/28/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$191,250
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	3	2/28/2023	NON-COMPETING CONTINUATION	-$191,250
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	1	1/23/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $223,353 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	003	3	7/27/2022	NON-COMPETING CONTINUATION	$231,250
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	2	4/7/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$186,061
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	2	5/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$7,897
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	1	4/7/2022	NEW	-$186,061
														Subtotal = $223,353

Issue Date FY: 2021 ( Subtotal = $277,500 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	1	9/27/2021	NEW	$277,500
														Subtotal = $277,500

Grand Total All Awards = $500,853

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Transcript-selective translational control of Th17 cell development and function

Award Number: R21AI154039

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: 09/27/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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