The Hippo pathway plays critical roles in cell growth, differentiation, organ development and tissue homeostasis, whereas its dysregulation can lead to tumorigenesis. YAP and TAZ are transcription co-activators and represent the main downstream effectors of the Hippo pathway. Here, we show that heat stress induces a strong and rapid YAP dephosphorylation and activation. The effect of heat shock on YAP is dominant to other signals known to modulate the Hippo pathway. Heat shock inhibits LATS kinase by promoting HSP90-dependent LATS interaction with and inactivation by protein phosphatase 5. Heat shock also induces LATS ubiquitination and degradation. YAP and TAZ are crucial for cellular heat shock responses, including the heat shock transcriptome and cell viability. This study uncovers previously unknown mechanisms of Hippo regulation by heat shock, as well as physiological functions of YAP, in the heat stress response. Our observations also reveal a potential combinational therapy involving hyperthermia and targeting of the Hippo pathway.

Hippo 通路在细胞生长、分化、器官发育和组织稳态中发挥着关键作用，而其失调可导致肿瘤发生。 YAP 和 TAZ 是转录共激活因子，代表 Hippo 通路的主要下游效应子。在这里，我们发现热应激会诱导强烈且快速的 YAP 去磷酸化和激活。热休克对 YAP 的影响比已知调节 Hippo 通路的其他信号占主导地位。热休克通过促进 HSP90 依赖性 LATS 与蛋白磷酸酶 5 的相互作用以及蛋白磷酸酶 5 的失活来抑制 LATS 激酶。热休克还诱导 LATS 泛素化和降解。 YAP 和 TAZ 对于细胞热休克反应至关重要，包括热休克转录组和细胞活力。这项研究揭示了以前未知的 Hippo 通过热休克调节的机制，以及 YAP 在热应激反应中的生理功能。我们的观察还揭示了一种潜在的联合疗法，涉及热疗和针对 Hippo 通路的靶向。