PMID- 22576015
OWN - NLM
STAT- MEDLINE
DCOM- 20130103
LR  - 20230815
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 8
IP  - 6
DP  - 2012 Jun
TI  - MTORC1 functions as a transcriptional regulator of autophagy by preventing 
      nuclear transport of TFEB.
PG  - 903-14
LID - 10.4161/auto.19653 [doi]
AB  - 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.
FAU - Martina, Jose A
AU  - Martina JA
AD  - Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD USA.
FAU - Chen, Yong
AU  - Chen Y
FAU - Gucek, Marjan
AU  - Gucek M
FAU - Puertollano, Rosa
AU  - Puertollano R
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20120511
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (14-3-3 Proteins)
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (TFEB protein, human)
RN  - 17885-08-4 (Phosphoserine)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - 14-3-3 Proteins/metabolism
MH  - Amino Acid Sequence
MH  - Autophagy/*genetics
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/chemistry/*metabolism
MH  - Cell Nucleus/*metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Models, Biological
MH  - Molecular Sequence Data
MH  - Multiprotein Complexes
MH  - Phagosomes/metabolism
MH  - Phosphorylation
MH  - Phosphoserine/metabolism
MH  - Protein Binding
MH  - Protein Transport
MH  - Proteins/antagonists & inhibitors/*metabolism
MH  - Subcellular Fractions/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - *Transcription, Genetic
PMC - PMC3427256
EDAT- 2012/05/12 06:00
MHDA- 2013/01/04 06:00
PMCR- 2013/06/01
CRDT- 2012/05/12 06:00
PHST- 2012/05/12 06:00 [entrez]
PHST- 2012/05/12 06:00 [pubmed]
PHST- 2013/01/04 06:00 [medline]
PHST- 2013/06/01 00:00 [pmc-release]
AID - 19653 [pii]
AID - 2011AUTO0473R1 [pii]
AID - 10.4161/auto.19653 [doi]
PST - ppublish
SO  - Autophagy. 2012 Jun;8(6):903-14. doi: 10.4161/auto.19653. Epub 2012 May 11.