CDKN1B/p27 regulates autophagy via the control of Ragulator and MTOR activity in amino acid-deprived cells

Abstract

The tumor suppressor CDKN1B/p27^Kip1 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.

Keywords: CDKN1B/p27/Kip1; LAMTOR1; Ragulator; autophagy; cell cycle; cell growth; mTOR.

Figure 1.

CDKN1B couples the cell growth and cell cycle machineries in amino acid-deprived cells. Under full-nutrient conditions (left panel), CDKN1B shuttles between the nucleus and cytoplasm, controlling cell cycle progression. Amino acids promote Ragulator-dependent RRAG activation and subsequent recruitment of MTORC1 to lysosomes, where MTORC1 is activated, leading to induction of cell growth. Activated RRAGs also recruit TFEB to lysosomes, preventing its translocation to the nucleus and induction of pro-autophagic and pro-apoptotic genes. During prolonged amino acid starvation (right panel), a fraction of CDKN1B translocates to the lysosomal surface, where it binds to the Ragulator subunit LAMTOR1, which prevents the assembly of the Ragulator-RRAG complex, precluding the recruitment of MTORC1 to lysosomes and its activation. TFEB accumulates in the nucleus and drives the expression of genes promoting autophagy and apoptosis. The figure was created using the vector image bank from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License