Cellular Mechanotransduction Relies on Tension-Induced and Chaperone-Assisted Autophagy
Cellular Mechanotransduction Relies on Tension-Induced and Chaperone-Assisted Autophagy
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DOI：
10.1016/j.cub.2013.01.064
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发表时间：
2013-03-04
期刊：
影响因子：
9.2
通讯作者：
Hoehfeld, Joerg
中科院分区：
文献类型：
--
作者：
Ulbricht, Anna;Eppler, Felix J.;Hoehfeld, Joerg
机械张力是运动、心血管、呼吸和泌尿生殖系统发育和稳态所必需的一种始终存在的生理刺激[1，2]。张力感应有助于干细胞分化、免疫细胞募集和肿瘤发生[3，4]。然而，机械信号如何在细胞内转导仍然知之甚少。在这里，我们确定分子伴侣辅助选择性自噬（CASA）作为肌肉和免疫细胞中机械转导所必需的张力诱导的自噬途径。CASA复合物由分子伴侣Hsc 70和HspB 8以及辅伴侣BAG 3组成，感测肌动蛋白交联蛋白细丝蛋白的机械展开。与伴侣蛋白相关的泛素连接酶CHIP一起，该复合物启动受损细丝蛋白的泛素依赖性自噬分选至溶酶体以进行降解。CASA期间自噬体的形成取决于BAG 3与突触足蛋白-2（SYNPO 2）的相互作用。这种相互作用由BAG 3 WW结构域介导，并促进与自噬体膜融合复合物的合作。BAG 3还利用其WW结构域参与雅普/TAZ信号传导。通过该途径，BAG 3刺激细丝蛋白转录以在机械张力下维持肌动蛋白锚定和交联。通过整合张力传感，自噬体形成和转录调节在机械转导，CASA机制确保组织稳态和调节基本的细胞过程，如粘附，迁移和增殖。
Mechanical tension is an ever-present physiological stimulus essential for the development and homeostasis of locomotory, cardiovascular, respiratory, and urogenital systems [1, 2]. Tension sensing contributes to stem cell differentiation, immune cell recruitment, and tumorigenesis [3, 4]. Yet, how mechanical signals are transduced inside cells remains poorly understood. Here, we identify chaperone-assisted selective autophagy (CASA) as a tension-induced autophagy pathway essential for mechanotransduction in muscle and immune cells. The CASA complex, comprised of the molecular chaperones Hsc70 and HspB8 and the cochaperone BAG3, senses the mechanical unfolding of the actin-crosslinking protein filamin. Together with the chaperone-associated ubiquitin ligase CHIP, the complex initiates the ubiquitin-dependent autophagic sorting of damaged filamin to lysosomes for degradation. Autophagosome formation during CASA depends on an interaction of BAG3 with synaptopodin-2 (SYNPO2). This interaction is mediated by the BAG3 WW domain and facilitates cooperation with an autophagosome membrane fusion complex. BAG3 also utilizes its WW domain to engage in YAP/TAZ signaling. Via this pathway, BAG3 stimulates filamin transcription to maintain actin anchoring and crosslinking under mechanical tension. By integrating tension sensing, autophagosome formation, and transcription regulation during mechanotransduction, the CASA machinery ensures tissue homeostasis and regulates fundamental cellular processes such as adhesion, migration, and proliferation.