LBCMCP, Centre de Biologie Intégrative, Université de Toulouse , Toulouse Cedex, France.
Autophagy. 2020 Dec;16(12):2297-2298. doi: 10.1080/15548627.2020.1831217. Epub 2020 Oct 12.
The tumor suppressor CDKN1B/p27 binds to and inhibits cyclin-CDK complexes in the nucleus, inducing cell cycle arrest. However, when in the cytoplasm, CDKN1B may promote tumorigenesis. Notably, cytoplasmic CDKN1B was reported to promote macroautophagy/autophagy in response to nutrient shortage by a previously unknown mechanism. In our recent work, we found that during prolonged amino acid starvation, CDKN1B promotes autophagy via an MTORC1-dependent pathway. A fraction of CDKN1B translocates to lysosomes, where it interacts with the Ragulator subunit LAMTOR1, preventing Ragulator assembly, which is required for MTORC1 activation in response to amino acids. Therefore, CDKN1B represses MTORC1 activity, leading to nuclear translocation of the transcription factor TFEB and activation of lysosomal function, enhancing starvation-induced autophagy flux and apoptosis. In contrast, cells lacking CDKN1B survive starvation despite reduced autophagy, due to elevated MTORC1 activation. These findings reveal that, by directly repressing MTORC1 activity, CDKN1B couples the cell cycle and cell growth machineries during metabolic stress.
肿瘤抑制因子 CDKN1B/p27 与细胞核中的细胞周期蛋白-CDK 复合物结合并抑制其活性，从而诱导细胞周期停滞。然而，当位于细胞质中时，CDKN1B 可能会促进肿瘤的发生。值得注意的是，据报道，细胞质 CDKN1B 通过一种先前未知的机制，在响应营养物质缺乏时促进巨自噬/自噬。在我们最近的工作中，我们发现，在长时间的氨基酸饥饿期间，CDKN1B 通过 MTORC1 依赖性途径促进自噬。CDKN1B 的一部分易位到溶酶体，在那里它与 Ragulator 亚基 LAMTOR1 相互作用，阻止 Ragulator 组装，这是 MTORC1 对氨基酸反应激活所必需的。因此，CDKN1B 抑制 MTORC1 活性，导致转录因子 TFEB 向核内易位并激活溶酶体功能，增强饥饿诱导的自噬流和细胞凋亡。相比之下，缺乏 CDKN1B 的细胞尽管自噬减少，但由于 MTORC1 激活增加，仍能在饥饿中存活。这些发现表明，CDKN1B 通过直接抑制 MTORC1 活性，在代谢应激期间将细胞周期和细胞生长机制偶联在一起。
