Autophagy is a catabolic process whereby cytoplasmic components are degraded within lysosomes, allowing cells to maintain energy homeostasis during nutrient depletion. Several studies reported that the CDK inhibitor p27^Kip1 promotes starvation-induced autophagy by an unknown mechanism. Here we find that p27 controls autophagy via an mTORC1-dependent mechanism in amino acid-deprived cells. During prolonged starvation, a fraction of p27 is recruited to lysosomes, where it interacts with LAMTOR1, a component of the Ragulator complex required for mTORC1 activation. Binding of p27 to LAMTOR1 prevents Ragulator assembly and mTORC1 activation, promoting autophagy. Conversely, p27^−/− cells exhibit elevated mTORC1 signalling as well as impaired lysosomal activity and autophagy. This is associated with cytoplasmic sequestration of TFEB, preventing induction of the lysosomal genes required for lysosome function. LAMTOR1 silencing or mTOR inhibition restores autophagy and induces apoptosis in p27^−/− cells. Together, these results reveal a direct coordinated regulation between the cell cycle and cell growth machineries.

自噬是一种分解代谢过程，细胞质成分在溶酶体内降解，使细胞在营养耗尽期间保持能量稳态。几项研究报告说，CDK 抑制剂 p27 ^Kip1通过未知机制促进饥饿诱导的自噬。在这里，我们发现 p27 通过氨基酸剥夺细胞中的 mTORC1 依赖性机制控制自噬。在长期饥饿期间，一部分 p27 被募集到溶酶体中，在那里它与 LAMTOR1 相互作用，LAMTOR1 是 mTORC1 激活所需的 Ragulator 复合物的一个组成部分。p27 与 LAMTOR1 的结合可防止 Ragulator 组装和 mTORC1 激活，从而促进自噬。相反，p27 ^-/-细胞表现出升高的 mTORC1 信号以及受损的溶酶体活性和自噬。这与 TFEB 的细胞质隔离有关，阻止诱导溶酶体功能所需的溶酶体基因。LAMTOR1 沉默或 mTOR 抑制可恢复自噬并诱导 p27 ^-/-细胞凋亡。总之，这些结果揭示了细胞周期和细胞生长机制之间的直接协调调节。