PMID- 34158631
OWN - NLM
STAT- MEDLINE
DCOM- 20220322
LR  - 20230204
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 28
IP  - 12
DP  - 2021 Dec
TI  - eIF4A3 regulates the TFEB-mediated transcriptional response via GSK3B to control 
      autophagy.
PG  - 3344-3356
LID - 10.1038/s41418-021-00822-y [doi]
AB  - During autophagy, the coordinated actions of autophagosomes and lysosomes result 
      in the controlled removal of damaged intracellular organelles and superfluous 
      substrates. The evolutionary conservation of this process and its requirement for 
      maintaining cellular homeostasis emphasizes the need to better dissect the 
      pathways governing its molecular regulation. In our previously performed 
      high-content screen, we assessed the effect of 1530 RNA-binding proteins on 
      autophagy. Among the top regulators, we identified the eukaryotic translation 
      initiation factor 4A-3 (eIF4A3). Here we show that depletion of eIF4A3 leads to a 
      potent increase in autophagosome and lysosome biogenesis and an enhanced 
      autophagic flux. This is mediated by the key autophagy transcription factor, 
      TFEB, which becomes dephosphorylated and translocates from the cytoplasm to the 
      nucleus where it elicits an integrated transcriptional response. We further 
      identified an exon-skipping event in the transcript encoding for the direct TFEB 
      kinase, GSK3B, which leads to a reduction in GSK3B expression and activity. 
      Through analysis of TCGA data, we found a significant upregulation of eIF4A3 
      expression across several cancer types and confirmed the potential relevance of 
      this newly identified signaling axis in human tumors. Hence, our data suggest a 
      previously unrecognized role for eIF4A3 as a gatekeeper of autophagy through the 
      control of TFEB activation, revealing a new mechanism for autophagy regulation.
CI  - (c) 2021. The Author(s), under exclusive licence to ADMC Associazione 
      Differenziamento e Morte Cellulare.
FAU - Sakellariou, Despoina
AU  - Sakellariou D
AUID- ORCID: 0000-0001-5894-7879
AD  - Danish Cancer Society Research Center, Copenhagen, Denmark.
FAU - Tiberti, Matteo
AU  - Tiberti M
AD  - Danish Cancer Society Research Center, Copenhagen, Denmark.
FAU - Kleiber, Thomas H
AU  - Kleiber TH
AD  - Danish Cancer Society Research Center, Copenhagen, Denmark.
FAU - Blazquez, Lorea
AU  - Blazquez L
AD  - Biodonostia Health Research Institute, San Sebastian, Spain.
AD  - Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
AD  - The Francis Crick Institute, London, UK.
FAU - Lopez, Aida Rodriguez
AU  - Lopez AR
AD  - Danish Cancer Society Research Center, Copenhagen, Denmark.
FAU - Abildgaard, Marie Holm
AU  - Abildgaard MH
AD  - Danish Cancer Society Research Center, Copenhagen, Denmark.
FAU - Lubas, Michal
AU  - Lubas M
AD  - Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, 
      Denmark.
FAU - Bartek, Jiri
AU  - Bartek J
AD  - Danish Cancer Society Research Center, Copenhagen, Denmark.
AD  - Department of Medical Biochemistry and Biophysics, Division of Genome Biology, 
      Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
FAU - Papaleo, Elena
AU  - Papaleo E
AD  - Danish Cancer Society Research Center, Copenhagen, Denmark.
AD  - Cancer Systems Biology, Section for Bioinformatics, Department of Health and 
      Technology, Technical University of Denmark, Lyngby, Denmark.
FAU - Frankel, Lisa B
AU  - Frankel LB
AUID- ORCID: 0000-0001-7249-3607
AD  - Danish Cancer Society Research Center, Copenhagen, Denmark. frankel@cancer.dk.
AD  - Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, 
      Denmark. frankel@cancer.dk.
LA  - eng
GR  - DFF-7016-00313/Det Frie Forskningsrad (Danish Council for Independent Research)/
GR  - DNRF 125/Danmarks Grundforskningsfond (Danish National Research Foundation)/
GR  - R272-2017-3872/Lundbeckfonden (Lundbeck Foundation)/
GR  - NNF19OC0056107/Novo Nordisk Fonden (Novo Nordisk Foundation)/
GR  - R209-A13011/Kraeftens Bekaempelse (Danish Cancer Society)/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210622
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (TFEB protein, human)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.7.- (Eukaryotic Initiation Factor-4A)
RN  - EC 3.6.1.- (EIF4A3 protein, human)
RN  - EC 3.6.4.13 (DEAD-box RNA Helicases)
SB  - IM
MH  - Autophagy
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*metabolism
MH  - DEAD-box RNA Helicases/*metabolism
MH  - Eukaryotic Initiation Factor-4A/*metabolism
MH  - Glycogen Synthase Kinase 3 beta/*metabolism
MH  - Humans
MH  - Transcription Factors/*metabolism
MH  - Transfection
PMC - PMC8630043
COIS- The authors declare no competing interests.
EDAT- 2021/06/24 06:00
MHDA- 2022/03/23 06:00
PMCR- 2022/12/01
CRDT- 2021/06/23 07:14
PHST- 2021/01/12 00:00 [received]
PHST- 2021/06/10 00:00 [accepted]
PHST- 2021/06/09 00:00 [revised]
PHST- 2021/06/24 06:00 [pubmed]
PHST- 2022/03/23 06:00 [medline]
PHST- 2021/06/23 07:14 [entrez]
PHST- 2022/12/01 00:00 [pmc-release]
AID - 10.1038/s41418-021-00822-y [pii]
AID - 822 [pii]
AID - 10.1038/s41418-021-00822-y [doi]
PST - ppublish
SO  - Cell Death Differ. 2021 Dec;28(12):3344-3356. doi: 10.1038/s41418-021-00822-y. 
      Epub 2021 Jun 22.