eIF4A3 regulates the TFEB-mediated transcriptional response via GSK3B to control autophagy

Despoina Sakellariou, Matteo Tiberti, Thomas H. Kleiber, Lorea Blazquez, Aida Rodríguez López, Marie Holm Abildgaard, Michal Lubas, Jiri Bartek, Elena Papaleo, Lisa B. Frankel*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


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.

Original languageEnglish
JournalCell Death and Differentiation
Pages (from-to)3344–3356
Publication statusPublished - 2021

Bibliographical note

Funding Information:
The work for this study was supported from The Lundbeck Foundation (R272-2017-3872), The Novo Nordisk Foundation (NNF19OC0056107), The Danish Cancer Society (R209-A13011), The Danish Council for Independent Research (DFF-7016-00313), and The Danish National Research Foundation (project CARD, DNRF 125).


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