HSP90 Chaperone Proteins and Interactors in Cellular Signal Transduction

在 2021 财年，(1)我们证实，选择性剪接的雄激素受体（缺乏与 Hsp90 相互作用的配体结合结构域）与 Hsp40 和 Hsp70 相互作用，并保持依赖于 Hsp40 和 Hsp70 的稳定性和转录活性。此外，我们还表明，靶向 Hsp40/Hsp70 伴侣轴是治疗对标准抗雄激素治疗产生耐药性的去势抵抗性前列腺癌的一种新策略。 (2) 我们鉴定了线粒体中由 Trap1、Hsp60 和线粒体 Hsp70 组成的多伴侣复合物，作为氧化磷酸化和 ATP 合酶介导的 ATP 产生的调节剂。多伴侣复合物的组装对线粒体 ATP 水平敏感。我们确定了 ATP 合酶的多个亚基和众多电子传递链组件作为 Trap1 相互作用子（潜在客户），并且我们证明 Trap1 敲除会导致氧化磷酸化增加，并强烈偏好谷氨酰胺作为 TCA 循环的主要碳源。 (3) 我们还证明，Hsp70 抑制通过导致 HSF1 不稳定，阻断热诱导和 Hsp90 抑制剂增强的 HSF1 激活和转录活性。我们发现 Hsp70 与 HSF1 单体（无活性）和三聚体（活性）结合。

In FY2021, (1)We confirmed that alternatively spliced androgen receptor (lacking ligand binding domain with which Hsp90 interacts) interacts with and remains dependent on Hsp40 and Hsp70 for stability and transcriptional activity. Further, we showed that targeting the Hsp40/Hsp70 chaperone axis is a novel strategy to treat castration-resistant prostate cancer that has become resistant to standard antiandrogen therapy. (2) We identified a multichaperone complex in mitochondria comprised of Trap1, Hsp60 and mitochondrial Hsp70 as a regulator of oxidative phosphorylation and ATP synthase-mediated ATP production. Assembly of the multichaperone complex is sensitive to mitochondrial ATP level. We identified multiple subunits of ATP synthase and numerous electron transport chain components as Trap1 interactors (potential clients), and we demonstrated that Trap1 knockout leads to increased oxidative phosphorylation and a strong preference for glutamine as the primary carbon source for the TCA cycle. (3) We also demonstrated that Hsp70 inhibition blocked both heat-induced and Hsp90 inhibitor-potentiated HSF1 activation and transcriptional activity by causing the destabilization of HSF1. We showed that Hsp70 bound to both HSF1 monomers (inactive) and trimers (active).