CDK4/6 regulate lysosome biogenesis through TFEB/TFE3

Abstract

Lysosomes are degradation and signaling organelles that adapt their biogenesis to meet many different cellular demands; however, it is unknown how lysosomes change their numbers for cell division. Here, we report that the cyclin-dependent kinases CDK4/6 regulate lysosome biogenesis during the cell cycle. Chemical or genetic inactivation of CDK4/6 increases lysosomal numbers by activating the lysosome and autophagy transcription factors TFEB and TFE3. CDK4/6 interact with and phosphorylate TFEB/TFE3 in the nucleus, thereby inactivating them by promoting their shuttling to the cytoplasm. During the cell cycle, lysosome numbers increase in S and G2/M phases when cyclin D turnover diminishes CDK4/6 activity. These findings not only uncover the molecular events that direct the nuclear export of TFEB/TFE3, but also suggest a mechanism that controls lysosome biogenesis in the cell cycle. CDK4/6 inhibitors promote autophagy and lysosome-dependent degradation, which has important implications for the therapy of cancer and lysosome-related disorders.

Dichotomous regulation of lysosomes by MYC and TFEB controls hematopoietic stem cell fate

“…Next, we examined the effects of modulating TFEB activity through altering the phosphorylation of the S142 and S211 sites that are known to be targeted by several kinases (mTORC1, CDK4/6, ERK1/2) (19,31). In nutrient-rich conditions, S142 and S211 phosphorylation of TFEB results in its cytoplasmic retention, whereas upon nutrient starvation, dephosphorylated TFEB translocates to the nucleus to induce the expression of lysosomal genes (13,19,31). Overexpression of a constitutively nuclear form of TFEB (TFEB S142A ), .…”

“…Next, we examined the effects of modulating TFEB activity through altering the phosphorylation of the S142 and S211 sites that are known to be targeted by several kinases (mTORC1, CDK4/6, ERK1/2) (19,31). In nutrient-rich conditions, S142 and S211 phosphorylation of TFEB results in its cytoplasmic retention, whereas upon nutrient starvation, dephosphorylated TFEB translocates to the nucleus to induce the expression of lysosomal genes (13,19,31). Overexpression of a constitutively nuclear form of TFEB (TFEB S142A ), generated through disruption of the S142 phosphorylation site, in CD34 + CD38 -hCB cells led to significant reduction of graft size in primary transplanted mice but a large 22-fold increase in the frequency of self-renewing stem cells ( Fig Silencing TFEB in CD34 + CD38 -hCB cells also resulted in smaller graft size in primary mouse recipients, but in contrast to the findings with TFEB-OE vectors, the reduced engraftment in the shTFEB group was now accompanied by a 2.8-fold reduction in stem cell frequency by serial LDA ( Fig.…”

Multifaceted activities of transcription factor EB in cancer onset and progression

“…Similarly, in Hela cells, TFEB deletion resulted in reduced Rb phosphorylation and the TFEBS142A active mutant increased the expression of CDK4 and CDK7 [61]. The direct transcriptional control of CDK4 by TFEB together with the recent observation that TFEB Ser142 residue is a substrate of CDK4 itself [50] in a p53-dependent manner [63]. Doxorubicin-mediated DNA damage promoted the activation of CDKN1A (CDK Inhibitor 1A) (p21) through TFEB, leading to cell cycle arrest [63].…”

MiT/TFE Family of Transcription Factors: An Evolutionary Perspective

“…In addition, CDK4/6 interacts with and phosphorylates TFEB/TFE3 in the nucleus of cells in G1 phase promoting TFEB/TFE3 inactivation and export to the cytoplasm. Conversely, low CDK4/6 activity during S–M phases results in TFEB and TFE3 activation and induction of lysosomal biogenesis and autophagy ( Yin et al, 2020 ).…”