小柯机器人

意大利帕多瓦大学Stefano Piccolo团队近期取得重要共作进展，他们研究发现基质细胞中的YAP/TAZ活性通过控制cGAS–STING来防止衰老。该项研究结果2022年6月29日在线发表于《自然》杂志上。

研究人员将衰老组织的结构和功能衰退与细胞机械信号传导的主要效应器YAP和TAZ的功能减弱联系起来。YAP/TAZ活性在基质细胞的生理衰老过程中下降，通过这些细胞中YAP/TAZ的基因失活来模拟这种下降会导致加速衰老。相反，维持YAP功能可使衰老细胞恢复活力，并阻止与生理衰老或由机械缺陷细胞外基质引发的加速衰老相关的衰老相关特征的出现。由YAP/TAZ失活诱导的衰老特征先于组织衰老的诱导。这是因为YAP/TAZ机械转导抑制了cGAS-STING信号传导，抑制STING可以防止YAP/TAZ失活后的组织衰老和过早衰老相关的组织退化。

从机制上讲，YAP/TAZ介导的cGAS-STING信号控制依赖于YAP/TAZ在保持核膜完整性方面的意想不到的作用，至少部分是通过直接转录调控核纤层蛋白B1（lamin B1）和ACTR2，后者参与了核周肌动蛋白帽的构建。研究结果表明，YAP/TAZ机械转导下降通过释放cGAS-STING信号（先天免疫的支柱）来驱动衰老。因此，维持YAP/TAZ机械信号或抑制STING可能是限制衰老相关炎症和改善健康衰老的有希望的方法。

据介绍，衰老与细胞衰老的诱导密切相关，但为什么会这样，人们还知之甚少。一个关键挑战是识别通常抑制衰老、在衰老过程中丢失并且在功能上与抗衰老相关的途径。

附：英文原文

Title: YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS–STING

Author: Sladitschek-Martens, Hanna Lucie, Guarnieri, Alberto, Brumana, Giulia, Zanconato, Francesca, Battilana, Giusy, Xiccato, Romy Lucon, Panciera, Tito, Forcato, Mattia, Bicciato, Silvio, Guzzardo, Vincenza, Fassan, Matteo, Ulliana, Lorenzo, Gandin, Alessandro, Tripodo, Claudio, Foiani, Marco, Brusatin, Giovanna, Cordenonsi, Michelangelo, Piccolo, Stefano

Issue&Volume: 2022-06-29

Abstract: Ageing is intimately connected to the induction of cell senescence1,2, but why this is so remains poorly understood. A key challenge is the identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing3. Here we connected the structural and functional decline of ageing tissues to attenuated function of the master effectors of cellular mechanosignalling YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of YAP/TAZ in these cells leads to accelerated ageing. Conversely, sustaining YAP function rejuvenates old cells and opposes the emergence of ageing-related traits associated with either physiological ageing or accelerated ageing triggered by a mechano-defective extracellular matrix. Ageing traits induced by inactivation of YAP/TAZ are preceded by induction of tissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS–STING signalling, to the extent that inhibition of STING prevents tissue senescence and premature ageing-related tissue degeneration after YAP/TAZ inactivation. Mechanistically, YAP/TAZ-mediated control of cGAS–STING signalling relies on the unexpected role of YAP/TAZ in preserving nuclear envelope integrity, at least in part through direct transcriptional regulation of lamin B1 and ACTR2, the latter of which is involved in building the peri-nuclear actin cap. The findings demonstrate that declining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS–STING signalling, a pillar of innate immunity. Thus, sustaining YAP/TAZ mechanosignalling or inhibiting STING may represent promising approaches for limiting senescence-associated inflammation and improving healthy ageing.

DOI: 10.1038/s41586-022-04924-6

Source: https://www.nature.com/articles/s41586-022-04924-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html