Department of Biochemistry and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
J Cell Biol. 2024 Sep 2;223(9). doi: 10.1083/jcb.202310049. Epub 2024 Jul 9.
Autophagy is essential for maintaining glucose homeostasis. However, the mechanism by which cells sense and respond to glucose starvation to induce autophagy remains incomplete. Here, we show that calcium serves as a fundamental triggering signal that connects environmental sensing to the formation of the autophagy initiation complex during glucose starvation. Mechanistically, glucose starvation instigates the release of vacuolar calcium into the cytoplasm, thus triggering the activation of Rck2 kinase. In turn, Rck2-mediated Atg11 phosphorylation enhances Atg11 interactions with Bmh1/2 bound to the Snf1-Sip1-Snf4 complex, leading to recruitment of vacuolar membrane-localized Snf1 to the PAS and subsequent Atg1 activation, thereby initiating autophagy. We also identified Glc7, a protein phosphatase-1, as a critical regulator of the association between Bmh1/2 and the Snf1 complex. We thus propose that calcium-triggered Atg11-Bmh1/2-Snf1 complex assembly initiates autophagy by controlling Snf1-mediated Atg1 activation in response to glucose starvation.
自噬对于维持葡萄糖内稳态至关重要。然而，细胞如何感知和响应葡萄糖饥饿以诱导自噬的机制仍不完整。在这里，我们表明钙作为一种基本的触发信号，将环境感应与葡萄糖饥饿期间自噬起始复合物的形成联系起来。在机制上，葡萄糖饥饿引发液泡钙释放到细胞质中，从而触发 Rck2 激酶的激活。反过来，Rck2 介导的 Atg11 磷酸化增强了与 Snf1-Sip1-Snf4 复合物结合的 Bmh1/2 与 Atg11 的相互作用，导致液泡膜定位的 Snf1 招募到 PAS 并随后激活 Atg1，从而启动自噬。我们还鉴定出 Glc7（一种蛋白磷酸酶-1）作为 Bmh1/2 和 Snf1 复合物之间关联的关键调节剂。因此，我们提出钙触发的 Atg11-Bmh1/2-Snf1 复合物组装通过控制 Snf1 介导的 Atg1 激活来响应葡萄糖饥饿启动自噬。
