Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
Center for Natural and Human Sciences, Federal University of ABC, São Bernardo do Campo, SP, Brazil.
Nat Commun. 2022 Jun 2;13(1):3074. doi: 10.1038/s41467-022-30751-4.
The formation of membraneless organelles can be a proteotoxic stress control mechanism that locally condenses a set of components capable of mediating protein degradation decisions. The breadth of mechanisms by which cells respond to stressors and form specific functional types of membraneless organelles, is incompletely understood. We found that Bcl2-associated athanogene 2 (BAG2) marks a distinct phase-separated membraneless organelle, triggered by several forms of stress, particularly hyper-osmotic stress. Distinct from well-known condensates such as stress granules and processing bodies, BAG2-containing granules lack RNA, lack ubiquitin and promote client degradation in a ubiquitin-independent manner via the 20S proteasome. These organelles protect the viability of cells from stress and can traffic to the client protein, in the case of Tau protein, on the microtubule. Components of these ubiquitin-independent degradation organelles include the chaperone HSP-70 and the 20S proteasome activated by members of the PA28 (PMSE) family. BAG2 condensates did not co-localize with LAMP-1 or p62/SQSTM1. When the proteasome is inhibited, BAG2 condensates and the autophagy markers traffic to an aggresome-like structure.
无膜细胞器的形成可以是一种蛋白质毒性应激控制机制，它局部浓缩了一组能够介导蛋白质降解决策的成分。细胞对应激原做出反应并形成特定功能类型的无膜细胞器的机制的广度尚未完全了解。我们发现 Bcl2 相关抗凋亡基因 2（BAG2）标记了一个独特的相分离无膜细胞器，由多种形式的应激触发，特别是高渗应激。与众所周知的凝聚物如应激颗粒和处理体不同，含 BAG2 的颗粒缺乏 RNA，缺乏泛素，并通过 20S 蛋白酶体以非泛素依赖的方式促进客户降解。这些细胞器可保护细胞免受应激的侵害，并且可以在微管上的 Tau 蛋白等情况下将客户蛋白运输到细胞器。这些非泛素依赖的降解细胞器的成分包括伴侣 HSP-70 和被 PA28（PMSE）家族成员激活的 20S 蛋白酶体。BAG2 凝聚物与 LAMP-1 或 p62/SQSTM1 不共定位。当蛋白酶体被抑制时，BAG2 凝聚物和自噬标记物会转移到类聚集体样结构中。
