磷脂酸信号的光学控制,ACS Central Science

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磷脂酸信号的光学控制
ACS Central Science ( IF 12.7 ) Pub Date : 2021-07-14 , DOI: 10.1021/acscentsci.1c00444
Reika Tei ₁ , Johannes Morstein ₂ , Andrej Shemet ₂ , Dirk Trauner ₂ , Jeremy M Baskin ₁

Affiliation

磷脂酸 (PA) 是甘油磷脂，可调节控制细胞生长和增殖的关键细胞信号通路，包括 mTOR 和 Hippo 通路。它们的酰基链在尾长和饱和度方面不同，导致不同 PA 物种的信号功能存在显着差异。例如，在 mTOR 信号传导中，PA 的饱和形式是抑制性的，而不饱和形式是激活性的。为了能够快速控制 PA 信号，我们在此描述了 PA 的光开关类似物的开发，称为AzoPA和dAzoPA，它们分别在一个或两个脂质尾部含有偶氮苯基团。这些光脂能够对其尾部结构进行光学控制，并且可以在直反式之间可逆地切换形式和相对弯曲的顺式形式。我们发现，顺式- dAzoPA选择性地激活mTOR信号，模仿的PA的不饱和形式的生物活性。此外，在 Hippo 信号传导（其生长抑制活性被 PA 阻断）的背景下，我们发现AzoPA和dAzoPA的顺式形式选择性抑制该途径。总的来说，这些光开关 PA 类似物能够对 mTOR 和 Hippo 信号进行光学控制，我们设想这些探针的未来应用来剖析生理和病理 PA 信号的多效性。

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Optical Control of Phosphatidic Acid Signaling

Phosphatidic acids (PAs) are glycerophospholipids that regulate key cell signaling pathways governing cell growth and proliferation, including the mTOR and Hippo pathways. Their acyl chains vary in tail length and degree of saturation, leading to marked differences in the signaling functions of different PA species. For example, in mTOR signaling, saturated forms of PA are inhibitory, whereas unsaturated forms are activating. To enable rapid control over PA signaling, we describe here the development of photoswitchable analogues of PA, termed AzoPA and dAzoPA, that contain azobenzene groups in one or both lipid tails, respectively. These photolipids enable optical control of their tail structure and can be reversibly switched between a straight trans form and a relatively bent cis form. We found that cis-dAzoPA selectively activates mTOR signaling, mimicking the bioactivity of unsaturated forms of PA. Further, in the context of Hippo signaling, whose growth-suppressing activity is blocked by PA, we found that the cis forms of both AzoPA and dAzoPA selectively inhibit this pathway. Collectively, these photoswitchable PA analogues enable optical control of mTOR and Hippo signaling, and we envision future applications of these probes to dissect the pleiotropic effects of physiological and pathological PA signaling.

更新日期：2021-07-28

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