Post-transcriptional regulation of ATG1 is a critical node that modulates autophagy during distinct nutrient stresses

Vikramjit Lahiri, Shree Padma Metur, Zehan Hu, Xinxin Song, Muriel Mari, Wayne D Hawkins, Janakraj Bhattarai, Elizabeth Delorme-Axford, Fulvio Reggiori, Daolin Tang, Joern Dengjel, Daniel J Klionsky*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
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Abstract

Macroautophagy/autophagy is a highly conserved nutrient-recycling pathway that eukaryotes utilize to combat diverse stresses including nutrient depletion. Dysregulation of autophagy disrupts cellular homeostasis leading to starvation susceptibility in yeast and disease development in humans. In yeast, the robust autophagy response to starvation is controlled by the upregulation of ATG genes, via regulatory processes involving multiple levels of gene expression. Despite the identification of several regulators through genetic studies, the predominant mechanism of regulation modulating the autophagy response to subtle differences in nutrient status remains undefined. Here, we report the unexpected finding that subtle changes in nutrient availability can cause large differences in autophagy flux, governed by hitherto unknown post-transcriptional regulatory mechanisms affecting the expression of the key autophagyinducing kinase Atg1 (ULK1/ULK2 in mammals). We have identified two novel post-transcriptional regulators of ATG1 expression, the kinase Rad53 and the RNA-binding protein Ded1 (DDX3 in mammals). Furthermore, we show that DDX3 regulates ULK1 expression post-transcriptionally, establishing mechanistic conservation and highlighting the power of yeast biology in uncovering regulatory mechanisms that can inform therapeutic approaches.

Original languageEnglish
Pages (from-to)1694-1714
Number of pages21
JournalAutophagy
Volume18
Issue number7
Early online date26-Nov-2021
DOIs
Publication statusPublished - 2022

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