HSP90 Chaperone Proteins and Interactors in Cellular Signal Transduction

在2021财年，(1)我们证实了选择性剪接的雄激素受体(缺少与Hsp90相互作用的配体结合域)与Hsp40和Hsp70相互作用，并仍然依赖于Hsp40和Hsp70的稳定性和转录活性。此外，我们发现，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耐药前列腺癌的一种新策略。(2)我们在线粒体中发现了一个由TRap1、Hsp60和线粒体Hsp70组成的多环蛋白复合体，作为氧化磷酸化和ATP合成酶介导的ATP合成的调节因子。多环蛋白复合体的组装对线粒体的ATP水平很敏感。我们发现ATP合成酶的多个亚基和大量的电子传递链组件是TRap1的相互作用因子(潜在客户)，我们证明了TRap1基因敲除导致氧化磷酸化增加，并强烈倾向于谷氨酰胺作为TCA循环的主要碳源。(3)我们还证明了Hsp70的抑制通过导致HSF1的失稳而阻断了热诱导和Hsp90抑制剂增强的HSF1的激活和转录活性。我们发现Hsp70既与HSF1单体结合(非活性)，也与三聚体结合(活性)。

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).