Acetylation as a novel post-translational modification of mafa
Ended Project Grant Awarded Last action
- Award ID
- F31DK137600
- Recipient
-
The Trustees Of Columbia University In The City Of New York UEI QHF5ZZ114M72
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $293,128
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date
- Place of performance
- New York, NY 10032, USA
Award details come from USAspending.gov.
Description
- Abstract
- SS-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 SS-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 SS-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 sscell 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 SS-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).
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $49,538 | |
| Amendment | $0 | |
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| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $47,694 | |
| Amendment | $47,694 | |
| Amendment | $47,694 | |
| Amendment | $47,694 | |
| Original award | $47,694 |
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Quick answers
Who received award F31DK137600?
F31DK137600 was awarded to The Trustees Of Columbia University In The City Of New York by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on August 14, 2024.
How much is award F31DK137600 worth?
$293,128 has been obligated on F31DK137600.
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