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Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase

Item Type:Article
Title:Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase
Creators Name:Guarani, V. and Deflorian, G. and Franco, C.A. and Krüger, M. and Phng, L.K. and Bentley, K. and Toussaint, L. and Dequiedt, F. and Mostoslavsky, R. and Schmidt, M.H.H. and Zimmermann, B. and Brandes, R.P. and Mione, M. and Westphal, C.H. and Braun, T. and Zeiher, A.M. and Gerhardt, H. and Dimmeler, S. and Potente, M.
Abstract:Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.
Keywords:Acetylation, Endothelial Cells, Gene Expression Regulation, Gene Knockout Techniques, Gene Silencing, HEK293 Cells, Mutation, Notch Receptor, Notch1 Receptor, Signal Transduction, Sirtuin 1, Animals, Mice, Zebrafish
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group (U.K.)
Volume:473
Number:7346
Page Range:234-238
Date:12 May 2011
Official Publication:https://doi.org/10.1038/nature09917
PubMed:View item in PubMed

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