EIF4A3 (eukaryotic translation initiation factor 4A3) is an RNA helicase and core component of the exon junction complex. While this RNA-binding protein (RBP) is well-characterized for its crucial roles in splicing, RNA trafficking and nonsense-mediated decay, its role in the regulation of metabolic signaling pathways remains elusive. In a recent study, we describe a new role for EIF4A3 as a negative regulator of macroautophagy/autophagy. Mechanistically, we report that EIF4A3, through its ability to safeguard splicing, can maintain low basal levels of autophagy through the cytosolic retention of the key autophagy transcription factor TFEB. Upon EIF4A3 depletion, the shuttling of TFEB to the nucleus results in an integrated transcriptional response, which induces both early and late steps of the autophagy pathway and enhances autophagic flux. We further report the upregulation of EIF4A3 across multiple cancer types and highlight the relevance of this newly identified EIF4A3-TFEB signaling axis in human tumors.
Keywords: Autophagy regulation; EIF4A3; GSK3B; RNA-binding proteins; TFEB; cancer; exon skipping.