Article

MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB

Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD USA.
Autophagy (Impact Factor: 11.75). 06/2012; 8(6):903-14. DOI: 10.4161/auto.19653
Source: PubMed

ABSTRACT

The mammalian target of rapamycin (MTOR) protein kinase complex is a key component of a pathway that regulates cell growth and proliferation in response to energy levels, hypoxia, nutrients and insulin. Inhibition of MTORC1 strongly induces autophagy by regulating the activity of the ULK protein kinase complex that is required for the formation of autophagosomes. However, the participation of MTORC1 in the expression of autophagy genes has not been characterized. Here we show that MTORC1 regulates nuclear localization and activity of the transcription factor EB (TFEB), a member of the bHLH leucine-zipper family of transcription factors that drives expression of autophagy and lysosomal genes. Under normal nutrient conditions, TFEB is phosphorylated in Ser211 in an MTORC1-dependent manner. This phosphorylation promotes association of TFEB with members of the YWHA (14-3-3) family of proteins and retention of the transcription factor in the cytosol. Pharmacological or genetic inhibition of MTORC1 causes dissociation of the TFEB/YWHA complex and rapid transport of TFEB to the nucleus where it increases transcription of multiple genes implicated in autophagy and lysosomal function. Active TFEB also associates with late endosomal/lysosomal membranes through interaction with the LAMTOR/RRAG/MTORC1 complex. Our results unveil a novel role for MTORC1 in the maintenance of cellular homeostasis by regulating autophagy at the transcriptional level.

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    • "Interestingly, mTORC1 regulates TFEB subcellular localization and activity. mTORC1-mediated phosphorylation of TFEB specific serine residues, which occurs on the lysosomal surface (Martina et al, 2012;Roczniak-Ferguson et al, 2012;Settembre et al, 2012), keeps TFEB inactive in the cytoplasm . Under nutrient-rich conditions, active mTORC1 promotes biosynthetic pathways and blocks autophagy. "

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    • "Further work is required to determine how TFEB is activated. TFEB can be phosphorylated by kinases such as mTORC1 and protein kinase Cb (Martina et al. 2012;Roczniak-Ferguson et al. 2012;Settembre et al. 2012;Ferron et al. 2013), with phosphorylation of serines being implicated in both preventing nuclear translocation of TFEB (Martina et al. 2012;Roczniak-Ferguson et al. 2012) and being required for the biological functions of TFEB (Pe~Llopis et al. 2011;Ferron et al. 2013). Since PINK1 is a serine/threonine kinase, it is a putative candidate for directly phosphorylating TFEB or initiating a kinase cascade to activate TFEB. "
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    • "In comparison to the partial rescue of muscle area achieved by other modifiers, such as mblC, DIAP1 overexpression or Atg gene silencing, the recovery obtained upon mTOR overexpression was complete. The fact that mTOR overexpression in model flies dramatically enhanced muscle area recovery and apoptosis activity could be due to the fact that mTOR, besides being a negative regulator of autophagy, regulates protein synthesis driving cell growth and proliferation (Martina et al., 2012). Consequently, the dramatic recovery of muscle area that we observed in model flies could be a combination of the activation of protein synthesis induced by mTOR overexpression and the negative regulation of autophagy. "
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