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; Peixin Yang

doi:10.1038/s41467-018-08268-6

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

Nat Commun. 2019 Jan 17;10(1):282. doi: 10.1038/s41467-018-08268-6.

Authors

Penghua Yang¹, Cheng Xu¹, E Albert Reece^{1

2}, Xi Chen¹, Jianxiang Zhong¹, Min Zhan³, Deborah J Stumpo⁴, Perry J Blackshear^{4

5}, Peixin Yang^{6

7}

Affiliations

¹ Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, 21201, MD, USA.
² Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, 21201, MD, USA.
³ Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, 21201, MD, USA.
⁴ Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA.
⁵ Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC, 27710, USA.
⁶ Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, 21201, MD, USA. pyang@fpi.umaryland.edu.
⁷ Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, 21201, MD, USA. pyang@fpi.umaryland.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetylation
Animals
Blood Glucose / metabolism
Cell Line
Diabetes Mellitus, Experimental / blood
Diabetes Mellitus, Experimental / chemically induced
Diabetes Mellitus, Experimental / complications*
Embryo, Mammalian
Endoplasmic Reticulum Stress
Female
Fetal Diseases / blood
Fetal Diseases / etiology
Fetal Diseases / pathology*
Humans
Lysine Acetyltransferase 5 / genetics
Lysine Acetyltransferase 5 / metabolism*
Male
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / pathology
Myristoylated Alanine-Rich C Kinase Substrate / genetics
Myristoylated Alanine-Rich C Kinase Substrate / metabolism*
Neural Tube Defects / etiology
Neural Tube Defects / pathology*
Neurulation
Phosphorylation
Pregnancy
Pregnancy in Diabetics / blood
Sirtuin 2 / genetics
Sirtuin 2 / metabolism*
Streptozocin / toxicity
Trans-Activators / genetics
Trans-Activators / metabolism*

Substances

Blood Glucose
Marcks protein, mouse
Trans-Activators
Myristoylated Alanine-Rich C Kinase Substrate
Streptozocin
Kat5 protein, mouse
Lysine Acetyltransferase 5
Sirt2 protein, mouse
Sirtuin 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding