Tip60- and sirtuin 2-regulated MARCKS acetylation and phosphorylation are required for diabetic embryopathy

Penghua Yang, Cheng Xu, E. Albert Reece, Xi Chen, Jianxiang Zhong, Min Zhan, Deborah J. Stumpo, Perry J. Blackshear and Peixin Yang ()
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Penghua Yang: University of Maryland School of Medicine
Cheng Xu: University of Maryland School of Medicine
E. Albert Reece: University of Maryland School of Medicine
Xi Chen: University of Maryland School of Medicine
Jianxiang Zhong: University of Maryland School of Medicine
Min Zhan: University of Maryland School of Medicine
Deborah J. Stumpo: National Institute of Environmental Health Sciences, Research Triangle Park
Perry J. Blackshear: National Institute of Environmental Health Sciences, Research Triangle Park
Peixin Yang: University of Maryland School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Failure of neural tube closure results in severe birth defects and can be induced by high glucose levels resulting from maternal diabetes. MARCKS is required for neural tube closure, but the regulation and of its biological activity and function have remained elusive. Here, we show that high maternal glucose induced MARCKS acetylation at lysine 165 by the acetyltransferase Tip60, which is a prerequisite for its phosphorylation, whereas Sirtuin 2 (SIRT2) deacetylated MARCKS. Phosphorylated MARCKS dissociates from organelles, leading to mitochondrial abnormalities and endoplasmic reticulum stress. Phosphorylation dead MARCKS (PD-MARCKS) reversed maternal diabetes-induced cellular organelle stress, apoptosis and delayed neurogenesis in the neuroepithelium and ameliorated neural tube defects. Restoring SIRT2 expression in the developing neuroepithelium exerted identical effects as those of PD-MARCKS. Our studies reveal a new regulatory mechanism for MARCKS acetylation and phosphorylation that disrupts neurulation under diabetic conditions by diminishing the cellular organelle protective effect of MARCKS.

Date: 2019
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DOI: 10.1038/s41467-018-08268-6

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