Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.
Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.
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DOI：
10.1038/nature09917
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发表时间：
2011-05-12
期刊：
影响因子：
64.8
通讯作者：
Potente M
中科院分区：
文献类型：
--
作者：
Guarani V;Deflorian G;Franco CA;Krüger M;Phng LK;Bentley K;Toussaint L;Dequiedt F;Mostoslavsky R;Schmidt MHH;Zimmermann B;Brandes RP;Mione M;Westphal CH;Braun T;Zeiher AM;Gerhardt H;Dimmeler S;Potente M
Notch信号传导是一种关键的细胞间通讯机制，对细胞特化和组织图案化至关重要，并协调血管生长的关键步骤。虽然Notch活性的细微变化足以引起内皮行为和血管形成的深刻差异，但对内皮Notch反应的调节和适应知之甚少。在这里，我们报告的NAD+依赖性脱乙酰酶SIRT1作为一个内在的负调制器的Notch信号在内皮细胞。我们发现，保守的赖氨酸上的Notch 1胞内结构域（NICD）的乙酰化通过改变NICD蛋白质的周转来控制Notch反应的幅度和持续时间。SIRT1与NICD相关，并作为NICD脱乙酰酶发挥作用，其对抗乙酰化诱导的NICD稳定。因此，缺乏SIRT1活性的内皮细胞对Notch信号传导敏感，导致生长受损，芽伸长和增强的Notch靶基因表达响应DLL4刺激，从而促进非发芽，茎细胞样表型。我们的研究结果将NICD的可逆乙酰化确定为适应Notch信号传导动力学的分子机制，并表明SIRT1作为变阻器微调内皮Notch反应。
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.