Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA.
Mol Cell. 2023 Sep 7;83(17):3155-3170.e8. doi: 10.1016/j.molcel.2023.07.019. Epub 2023 Aug 17.
The Hippo pathway is known for its crucial involvement in development, regeneration, organ size control, and cancer. While energy stress is known to activate the Hippo pathway and inhibit its effector YAP, the precise role of the Hippo pathway in energy stress response remains unclear. Here, we report a YAP-independent function of the Hippo pathway in facilitating autophagy and cell survival in response to energy stress, a process mediated by its upstream components MAP4K2 and STRIPAK. Mechanistically, energy stress disrupts the MAP4K2-STRIPAK association, leading to the activation of MAP4K2. Subsequently, MAP4K2 phosphorylates ATG8-family member LC3, thereby facilitating autophagic flux. MAP4K2 is highly expressed in head and neck cancer, and its mediated autophagy is required for head and neck tumor growth in mice. Altogether, our study unveils a noncanonical role of the Hippo pathway in energy stress response, shedding light on this key growth-related pathway in tissue homeostasis and cancer.
Hippo 通路在发育、再生、器官大小控制和癌症中起着至关重要的作用。虽然能量应激已知会激活 Hippo 通路并抑制其效应物 YAP，但 Hippo 通路在能量应激反应中的确切作用仍不清楚。在这里，我们报告了 Hippo 通路在能量应激下促进自噬和细胞存活的 YAP 非依赖性功能，该过程由其上游组件 MAP4K2 和 STRIPAK 介导。在机制上，能量应激破坏了 MAP4K2-STRIPAK 复合物的形成，导致 MAP4K2 的激活。随后，MAP4K2 磷酸化 ATG8 家族成员 LC3，从而促进自噬体流。MAP4K2 在头颈部癌症中高度表达，其介导的自噬对于小鼠头颈部肿瘤的生长是必需的。总之，我们的研究揭示了 Hippo 通路在能量应激反应中的非典型作用，为这条与组织稳态和癌症密切相关的关键生长相关通路提供了新的认识。
