Bhattacharya Kaushik, Picard Didier
Département de Biologie Cellulaire, Université de Genève, Sciences III, 1211, Genève 4, Switzerland.
Cell Mol Life Sci. 2021 Dec;78(23):7257-7273. doi: 10.1007/s00018-021-03962-z. Epub 2021 Oct 22.
The Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate ("client") transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.
Hsp70和Hsp90分子伴侣系统是真核生物在正常和应激条件下蛋白质稳态（蛋白平衡）的关键调节因子。Hsp70和Hsp90系统在物理和功能上相互作用，以确保细胞的蛋白平衡。共伴侣与Hsp70和Hsp90相互作用，以调节并促进它们的分子伴侣功能。哺乳动物的Hop，也称为Stip1，及其在芽殖酵母中的直系同源物Sti1是真核生物特有的共伴侣，它们被认为对于底物（“客户”）从Hsp70转移到Hsp90至关重要。作为三元复合物的一部分，Hop能够同时与Hsp70和Hsp90相互作用，从而促进底物转移。有趣的是，在缺乏Hop直系同源物的原核生物中，Hsp70和Hsp90的直系同源物直接相互作用。最近的证据表明，在没有Hop的情况下，真核生物的Hsp70和Hsp90也可以形成类似原核生物的二元伴侣复合物，并且这种二元复合物表现出增强的蛋白质折叠和抗聚集活性。典型的Hsp70-Hop-Hsp90三元伴侣复合物对于一小部分客户蛋白（包括糖皮质激素受体、酪氨酸激酶v-Src和26S/30S蛋白酶体）的最佳成熟和稳定性至关重要。虽然许多癌症中Hop的水平升高，但在衰老的人脑中Hop的水平会降低。由于Hop在所有真核细胞和生物体中并非必不可少，因此调节Hop的水平或活性可能对癌症和神经退行性疾病的治疗有益。
