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Acetylation as a novel post-translational modification of MafA

Award Number: F31DK137600
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Acetylation as a novel post-translational modification of MafA - PROJECT SUMMARY/ABSTRACT β-cell dysfunction is one of the hallmark determinants of Type II Diabetes (T2D) which is characterized by impaired insulin secretion and subsequent hyperglycemia. Identifying mechanisms to preserve and enhance β-cell function is therefore crucial to ameliorate T2D pathogenesis. Data from knockout animals has established that the MAF bZIP transcription factor A (MafA) is a critical regulator of β-cell functional capacity to adapt to insulin resistance. MafA directly activates insulin transcription, but also regulates a wide array of genes necessary for glucose sensing and insulin secretion. Commensurately, MafA is downregulated in islets of people and mice with T2D. Preserving MafA expression in islets from diabetic animals restores proper glucose regulation, suggesting that finding mechanisms to protect and enhance MafA expression may mitigate βcell dysfunction in T2D. MafA binds lysine acetyltransferases, Kat2b and CBP, leading to increased transactivation of MafA target genes, but the underlying mechanism is not known. Testing the hypothesis that Kat2b/CBP may acetylate MafA , I performed a LC/MS-MS screen that revealed MafA acetylation at lysines 32, 33 and 255. Based on this result, I mutated these lysines to glutamine (3KQ) and arginine (3KR) to mimic constitutively acetylated and deacetylated MafA, respectively. Using these mimetics, I found that 3KQ MafA has significantly increased transactivation ability at the insulin promoter. As a first step to understanding mechanism of this increased transactivation ability, I observed that MafA acetylation prompts hyperphosphorylation at serine 14 and competes with SUMOylation at lysine 32. These data suggest a novel form of PTM crosstalk between MafA acetylation, phosphorylation and SUMOylation. In Aim 1, I use my recently generated 3KQ and 3KR knock-in mice, and human beta cell lines, to determine whether MafA acetylation may affect GSIS and improve the β-cell response to obesity-induced insulin resistance. In Aim 2, I explore the complex relationship between MafA PTMs, and test whether acetylation- induced hyperphosphorylation is necessary for activity (Aim 2a) and whether a SUMOylation-acetylation switch occurs in response to rising glucose levels (Aim 2b).


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 = $49,538 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	8/21/2025	NON-COMPETING CONTINUATION	$49,538
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	7/28/2025	OTHER REVISION	$0
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/14/2025	TERMINATION	$0
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	4/29/2024	NEW	$0
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	4/29/2024	NEW	$1,280
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/14/2024	NEW	$47,694
														Subtotal = $48,974

Grand Total All Awards = $98,512

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Acetylation as a novel post-translational modification of MafA

Award Number: F31DK137600

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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