A large-scale analysis of autophagy-related gene expression identifies new regulators of autophagy

Abstract

Autophagy is a pathway mediating vacuolar degradation and recycling of proteins and organelles, which plays crucial roles in cellular physiology. To ensure its proper cytoprotective function, the induction and amplitude of autophagy are tightly regulated, and defects in its regulation are associated with various diseases. Transcriptional control of autophagy is a critical aspect of autophagy regulation, which remains largely unexplored. In particular, very few transcription factors involved in the activation or repression of autophagy-related gene expression have been characterized. To identify such regulators, we analyzed the expression of representative ATG genes in a large collection of DNA-binding mutant deletion strains in growing conditions as well as after nitrogen or glucose starvation. This analysis identified several proteins involved in the transcriptional control of ATG genes. Further analyses showed a correlation between variations in expression and autophagy magnitude, thus identifying new positive and negative regulators of the autophagy pathway. By providing a detailed analysis of the regulatory network of the ATG genes our study paves the way for future research on autophagy regulation and signaling.

Transcriptional and post-transcriptional regulation of autophagy in the yeast Saccharomyces cerevisiae

“…When cells are starved, Gln3 positively regulates non-selective autophagy by targeting ATG14 (78), 7, 8, 9, 29, and 32 (69). Unexpectedly, in nutrient-replete conditions, deletion of GLN3 results in the accumulation of ATG8 and ATG29 transcripts, demonstrating either direct or indirect negative control over basal autophagy (69).…”

“…During growing conditions, Gcn4 positively mediates delivery of precursor aminopeptidase I in the Cvt pathway (69). When cells undergo starvation, Gcn4 regulates nonselective autophagy activity through ATG gene transcription (69). Gcn4 activates ATG1, ATG13 and ATG14 gene expression during amino acid deprivation (68), and ATG1 during nitrogen starvation (69).…”

“…Gln3 binds to the consensus sequence 5'-GATAAG-3' and 5'-GATTAG-3', which have been previously identified as nitrogen-responsive upstream activation sequences within the promoter regions of target genes (77). During rich conditions, Gln3 mediates biosynthetic delivery of precursor aminopeptidase I to the vacuole (69). When cells are starved, Gln3 positively regulates non-selective autophagy by targeting ATG14 (78), 7, 8, 9, 29, and 32 (69).…”

“…Gcn4 was initially identified to function in the amino acid starvation response and has been described as a principal regulator of autophagy gene expression (68). During growing conditions, Gcn4 positively mediates delivery of precursor aminopeptidase I in the Cvt pathway (69). When cells undergo starvation, Gcn4 regulates nonselective autophagy activity through ATG gene transcription (69).…”

“…When cells undergo starvation, Gcn4 regulates nonselective autophagy activity through ATG gene transcription (69). Gcn4 activates ATG1, ATG13 and ATG14 gene expression during amino acid deprivation (68), and ATG1 during nitrogen starvation (69). Gcn4 controls ATG41 mRNA expression during nitrogen-starvation induced autophagy through transcriptional activation (70).…”