纪念斯隆-凯特琳癌症中心Philipp Niethammer小组宣布他们的研究显示，内质网破坏刺激核膜机械转导。2025年12月9日，国际知名学术期刊《自然—细胞生物学》发表了这一成果。

为了测试ER是否缓冲了TINM，课题组人员创造了基因编码的Ca²⁺-不敏感的TINM生物传感器两亲脂质填充结构域（ALPIN）。ALPIN -或cPLA₂-INM相互作用的共聚焦延时成像，以及内质网形态、核形状/体积和细胞裂解，揭示了在渗透或铁致应激的哺乳动物细胞和斑马鱼伤口边缘中，TINM与内质网核膜连续破坏之间的联系。通过将ALPIN成像与Ca²⁺诱导的内质网破坏相结合，课题组揭示了这种相关性的连续性，这表明内质网的代偿性膜流缓冲了TINM，而不是阻止它。

除了巩固通过核变形激活cPLA₂的生物力学基础外，他们的研究结果还确定了细胞应激和细胞死亡诱导的内质网破坏是另一个核膜机械转导触发因素。

据介绍，胞质磷脂酶A2 （cPLA₂）通过从内核膜（INM）释放代谢前体花生四烯酸来控制脊椎动物中一些最强大的炎性脂质。Ca²⁺和INM张力（TINM）被认为控制着cPLA₂在INM上的相互作用和活性。然而，由于来自相邻内质网（ER）的代偿性膜流可能阻止TINM，因此允许cPLA₂或其他介质进行核膜机械转导的条件尚不清楚。

附：英文原文

Title: Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction

Author: Shen, Zhouyang, Gelashvili, Zaza, Niethammer, Philipp

Issue&Volume: 2025-12-09

Abstract: Cytosolic phospholipase A2 (cPLA2) controls some of the most powerful inflammatory lipids in vertebrates by releasing their metabolic precursor, arachidonic acid, from the inner nuclear membrane (INM). Ca2+ and INM tension (TINM) are thought to govern the interactions and activity of cPLA2 at the INM. However, as compensatory membrane flow from the contiguous endoplasmic reticulum (ER) may prevent TINM, the conditions permitting nuclear membrane mechanotransduction by cPLA2 or other mediators remain unclear. To test whether the ER buffers TINM, we created the genetically encoded, Ca2-insensitive TINM biosensor amphipathic lipid-packing domain inside the nucleus (ALPIN). Confocal time-lapse imaging of ALPIN– or cPLA2–INM interactions, along with ER morphology, nuclear shape/volume and cell lysis revealed a link between TINM and disrupted ER–nuclear membrane contiguity in osmotically or ferroptotically stressed mammalian cells and at zebrafish wound margins in vivo. By combining ALPIN imaging with Ca2+-induced ER disruption, we reveal the causality of this correlation, which suggests that compensatory membrane flow from the ER buffers TINM without preventing it. Besides consolidating the biomechanical basis of cPLA2 activation by nuclear deformation, our results identify cell stress- and cell death-induced ER disruption as an additional nuclear membrane mechanotransduction trigger.

DOI: 10.1038/s41556-025-01820-9

Source: https://www.nature.com/articles/s41556-025-01820-9