Chaperone-Assisted Selective Autophagy Is Essential for Muscle Maintenance
Chaperone-Assisted Selective Autophagy Is Essential for Muscle Maintenance
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DOI：
10.1016/j.cub.2009.11.022
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发表时间：
2010-01-26
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：
Arndt, Verena;Dick, Nikolaus;Hoehfeld, Joerg
在不断威胁蛋白质完整性的细胞环境中，生物结构是如何维持的？在这里，我们阐明了影响Z盘的蛋白质稳态机制，Z盘是横纹肌中肌动蛋白锚定所必需的蛋白质组装体，其在收缩期间受到机械，热和氧化应激[1]。基于果蝇cochaperone Starvin（Stv）的特性，我们定义了一个保守的Z盘维护所需的伴侣机制。这种机制不是保持Z盘蛋白处于折叠构象，而是通过分子伴侣辅助的选择性自噬（CASA）促进受损组分（如细丝蛋白）的降解。Stv及其哺乳动物直系同源物BAG-3协调Hsc 70和小的热休克蛋白HspB 8的活性，在处置过程中由伴侣相关的泛素连接酶CHIP和自噬泛素衔接子p62启动。因此，CASA与分子伴侣介导的自噬不同，后者先前显示促进客户端跨溶酶体膜的不依赖于泛素的直接易位[2]。受损的CASA导致果蝇、小鼠和人的Z盘崩解和进行性肌无力。我们的研究结果揭示了分子伴侣辅助降解对保护细胞结构的重要性，并将肌肉确定为高度依赖于完整蛋白质稳态网络的组织，从而揭示了各种肌病和衰老。
How are biological structures maintained in a cellular environment that constantly threatens protein integrity? Here we elucidate proteostasis mechanisms affecting the Z disk, a protein assembly essential for actin anchoring in striated muscles, which is subjected to mechanical, thermal, and oxidative stress during contraction [1]. Based on the characterization of the Drosophila melanogaster cochaperone Starvin (Stv), we define a conserved chaperone machinery required for Z disk maintenance. Instead of keeping Z disk proteins in a folded conformation, this machinery facilitates the degradation of damaged components, such as filamin, through chaperone-assisted selective autophagy (CASA). Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the small heat shock protein HspB8 during disposal that is initiated by the chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62. CASA is thus distinct from chaperone-mediated autophagy, previously shown to facilitate the ubiquitin-independent, direct translocation of a client across the lysosomal membrane [2]. Impaired CASA results in Z disk disintegration and progressive muscle weakness in flies, mice, and men. Our findings reveal the importance of chaperone-assisted degradation for the preservation of cellular structures and identify muscle as a tissue that highly relies on an intact proteostasis network, thereby shedding light on diverse myopathies and aging.