Tip60- and sirtuin 2-regulated MARCKS acetylation and phosphorylation are required for diabetic embryopathy
PublisherNature Publishing Group
MetadataShow full item record
AbstractFailure 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. ©2019, The Author(s).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85060149339&doi=10.1038%2fs41467-018-08268-6&partnerID=40&md5=1060d6b8b72ba62476ced0d97c99db23; http://hdl.handle.net/10713/8641
- High glucose-induced oxidative stress represses sirtuin deacetylase expression and increases histone acetylation leading to neural tube defects.
- Authors: Yu J, Wu Y, Yang P
- Issue date: 2016 May
- Superoxide dismutase 2 overexpression alleviates maternal diabetes-induced neural tube defects, restores mitochondrial function and suppresses cellular stress in diabetic embryopathy.
- Authors: Zhong J, Xu C, Gabbay-Benziv R, Lin X, Yang P
- Issue date: 2016 Jul
- Modulation of nuclear factor-κB signaling and reduction of neural tube defects by quercetin-3-glucoside in embryos of diabetic mice.
- Authors: Tan C, Meng F, Reece EA, Zhao Z
- Issue date: 2018 Aug
- The increased activity of a transcription factor inhibits autophagy in diabetic embryopathy.
- Authors: Xu C, Chen X, Reece EA, Lu W, Yang P
- Issue date: 2019 Jan
- Disturbed intracellular calcium homeostasis in neural tube defects in diabetic embryopathy.
- Authors: Zhao Z, Cao L, Hernández-Ochoa E, Schneider MF, Reece EA
- Issue date: 2019 Jun 30