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

Abstract

Autophagy is a highly conserved catabolic pathway that is vital for development, cell survival, and the degradation of dysfunctional organelles and potentially toxic aggregates. Dysregulation of autophagy is associated with cancer, neurodegeneration, and lysosomal storage diseases. Accordingly, autophagy is precisely regulated at multiple levels (transcriptional, post-transcriptional, translational, and post-translational) to prevent aberrant activity. Various model organisms are used to study autophagy, but the baker's yeast Saccharomyces cerevisiae continues to be advantageous for genetic and biochemical analysis of non-selective and selective autophagy. In this Minireview, we focus on the cellular mechanisms that regulate autophagy transcriptionally and post-transcriptionally in S. cerevisiae.

Keywords: RNA degradation; autophagy; post-translational modification; transcription; vacuole; yeast.

Figure 1.

Autophagy regulation occurs at multiple levels. Because of the essential role that autophagy plays in maintaining homeostasis and the myriad of diseases that can result from perturbations to the pathway, cells must strictly modulate the entire process, beginning at transcription through post-translational modification. At the level of transcription, ATG gene expression can be regulated both positively and negatively through the action of specific transcription factors and epigenetic changes at histones. These transcripts can then be controlled further at the post-transcriptional and translational levels through the mechanisms of non-coding (nc) RNA, RNA-binding proteins (RBPs), mRNA localization, and RNA decay. At the protein level, post-translational modification such as phosphorylation, ubiquitination, acetylation, glycosylation, and protein–protein interactions can further regulate autophagy activity.

Figure 2.

Non-selective autophagy in S. cerevisiae. Autophagy occurs through a sequential series of events in the yeast S. cerevisiae, including induction and nucleation of the phagophore at the PAS, expansion of the phagophore, closure and maturation to form the autophagosome, autophagosome–vacuole fusion, and cargo degradation followed by efflux of the breakdown products.

Figure 3.

Summary of transcriptional and post-transcriptional regulatory factors in S. cerevisiae. A, during nutrient-replete conditions, TORC1 is active and negatively regulates key autophagy-promoting factors, such as Rim15, while activating negative regulatory elements, including the decapping enzyme Dcp2. Dcp2 mediates decapping of target transcripts for subsequent RNA degradation. Repressors such as Rph1, Ume6, and Pho23 bind the promoters of ATG7, ATG8, and ATG9, respectively, to maintain autophagy at a basal level. B, when autophagy is stimulated by an external stress, such as nitrogen or amino acid starvation, TORC1 becomes inactivated. This inhibition of TORC1 allows for the downstream activation of positive autophagy regulators. Activators such as Gcn4, Gln3, Gat1, and Yap1 bind to target genes for transcription as indicated. RNA decay mediators Dhh1, Dcp2, and Xrn1 no longer target ATG mRNAs for down-regulation; instead, these ATG transcripts are presumably translated to sustain autophagy.