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途径在细胞生长，分化，器官发育和组织动态平衡中起关键作用，而其失调可导致肿瘤发生。YAP和TAZ是转录共激活因子，代表河马途径的主要下游效应子。在这里，我们表明，热应激诱导强烈而迅速的YAP脱磷酸作用和激活。热休克对YAP的影响在其他已知可调控Hippo途径的信号中占主导地位。热激通过促进依赖HSP90的LATS与蛋白磷酸酶5相互作用并被其失活来抑制LATS激酶。热激还诱导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热激调节河马的机制，以及YAP在热应激反应中的生理功能。我们的观察结果还揭示了涉及热疗和靶向Hippo途径的潜在组合疗法。