Investigating the role of INO80 in Saccharomyces cerevisiae metabolic stress response

Abstract

Metabolic processes convert nutrients to energy and other useful macromolecules, enabling cell growth and proliferation. Changes to nutrient availability threaten these processes and various conserved metabolic stress response pathways have evolved to ensure survival in starvation conditions. In Eukaryotes, nitrogen starvation induces the non-selective autophagic degradation of cytoplasmic material and selective, receptor-mediated, turnover of organelles. The molecular underpinnings of non-selective autophagy are well understood, however transcriptional regulation of selective autophagy pathways is not fully elucidated. The evolutionarily conserved ATP-dependent chromatin remodelling complex INO80 regulates the chromatin architecture of genes and promoters. INO80 has been implicated in coordinating metabolic gene regulation, but the exact mechanism is not known. How epigenetics and other chromatin-based processes regulate autophagy and coordinate the metabolic stress response remains poorly understood. We set out to characterise the role of INO80 in the metabolic stress response. Here we report that in Saccharomyces cerevisiae the INO80 complex promotes selective autophagy. Using a combination of ubiquitin proteomics and cellular biology assays we show that loss of INO80 leads to defective mitophagy, ER-phagy and compromised turnover of ubiquitinated proteins. Transcriptomic analysis revealed that the INO80 complex controls the expression of the sub-telomeric COS genes which are associated with endosome-mediated protein turnover. Our functional analysis demonstrates that expression of the COS genes is required for autophagic degradation of mitochondria. Mechanistically, our analysis reveals that INO80 promotes COS expression, ubiquitinatedprotein turnover, and survival in starvation, by counteracting NAD+-dependent heterochromatic silencing by the SIR complex. We demonstrate that INO80 facilitates the acetylation of histone H3 N-terminal tails and the recruitment of the acetyl-CoA synthetase Acs2 at COS gene promoters. Our results describe an epigenetic pathway which connects metabolic stress response with the regulation of transcription from sub-telomeric chromatin. They suggest that chromatin regulation of gene expression by the INO80 complex links endosomal sorting with selective autophagy and ensures viability under metabolic stress conditions.