The yeast transcription factor Stb5 acts as a negative regulator of autophagy by modulating cellular metabolism

ABSTRACT

Macroautophagy/autophagy is a highly conserved pathway of cellular degradation and recycling that maintains cell health during homeostatic conditions and facilitates survival during stress. Aberrant cellular autophagy contributes to the pathogenesis of human diseases such as cancer, neurodegeneration, and cardiovascular, metabolic and lysosomal storage disorders. Despite decades of research, there remain unanswered questions as to how autophagy modulates cellular metabolism, and, conversely, how cellular metabolism affects autophagy activity. Here, we have identified the yeast metabolic transcription factor Stb5 as a negative regulator of autophagy. Chromosomal deletion of STB5 in the yeast Saccharomyces cerevisiae enhances autophagy. Loss of Stb5 results in the upregulation of select autophagy-related (ATG) transcripts under nutrient-replete conditions; however, the Stb5-mediated impact on autophagy occurs primarily through its effect on genes involved in NADPH production and the pentose phosphate pathway. This work provides insight into the intersection of Stb5 as a transcription factor that regulates both cellular metabolic responses and autophagy activity.

Abbreviations: bp, base pairs; ChIP, chromatin immunoprecipitation; G6PD, glucose-6-phosphate dehydrogenase; GFP, green fluorescent protein; IDR, intrinsically disordered region; NAD, nicotinamide adenine dinucleotide; NADP⁺, nicotinamide adenine dinucleotide phosphate; NADPH, nicotinamide adenine dinucleotide phosphate (reduced); ORF, open reading frame; PA, protein A; PCR, polymerase chain reaction; PE, phosphatidylethanolamine; PPP, pentose phosphate pathway; prApe1, precursor aminopeptidase I; ROS, reactive oxygen species; RT-qPCR, real-time quantitative PCR; SD, standard deviation; TF, transcription factor; TOR, target of rapamycin; WT, wild-type.

KEYWORDS:

• Ald6
• autophagosome
• NADPH
• pentose phosphate pathway
• Ymr315w
• Zwf1

Acknowledgements

We thank Drs. Aileen Ariosa and Zhangyuan Yin (University of Michigan) for helpful suggestions. We thank Chika Hara and Yusuke Kuwana (Niigata University, Japan) and Hala Khasawneh and Emily Solomon (Oakland University) for technical assistance.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2023.2228533

Additional information

Funding

This work was supported by a Cayman Chemical/Cayman Biomedical Research Institute/CABRI research grant and Oakland University startup funds (to EDA) and NIH grant GM131919 (to DJK).