在能量压力的应答中，Hippo通路非经典地促进自噬和细胞存活。
The Hippo pathway noncanonically drives autophagy and cell survival in response to energy stress.
发表日期：2023 Aug 17
作者：
Gayoung Seo, Clinton Yu, Han Han, Li Xing, Rebecca Elizabeth Kattan, Jeongmin An, Amrutha Kizhedathu, Bing Yang, Annabella Luo, Abigail L Buckle, Delia Tifrea, Robert Edwards, Lan Huang, Huai-Qiang Ju, Wenqi Wang
来源：
MOLECULAR CELL
摘要：
Hippo通路因其在发育、再生、器官大小控制和癌症中的重要参与而闻名。尽管已知能量应激能激活Hippo通路并抑制其效应因子YAP，但Hippo通路在能量应激应答中的精确作用仍不清楚。在这里，我们报告了Hippo通路在能量应激应答中无关YAP的功能，该过程通过其上游组分MAP4K2和STRIPAK介导的，促进自噬和细胞存活。在机械上，能量应激破坏了MAP4K2-STRIPAK的结合，导致MAP4K2的激活。随后，MAP4K2磷酸化ATG8家族成员LC3，从而促进自噬通量。在头颈癌中，MAP4K2的表达水平很高，并且其介导的自噬对小鼠头颈肿瘤生长起至关重要作用。总之，我们的研究揭示了Hippo通路在能量应激应答中的非经典作用，为组织稳态和癌症中的这一关键生长相关通路提供了启示。 版权所有 © 2023 Elsevier Inc. 保留所有权利。
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.Copyright © 2023 Elsevier Inc. All rights reserved.