Arg80 Orchestrates a Metabolic–Translational Proteostasis Network in S. cerevisiae

Proteostasis or protein homeostasis is essential for cellular function and organismal health. While many models of cytosolic proteostasis emphasize heat shock response as critical for regulating cellular protein folding, a comprehensive understanding of transcriptional modules that may regulate cytosolic protein folding is lacking. Through a focused screening for transcription factors, we provide evidence that a number of transcriptional programs unlinked to canonical proteotoxic response are involved in maintaining cellular homeostasis of protein folding. Among these, Arg80, a regulator of arginine metabolism, was activated during proteotoxic stress and found essential for mitigating it. We show that proteostasis imbalance in arg80Δ cells is caused by excess arginine accumulation, which is sufficient to impair protein folding. We reveal a complex interplay between arginine repression (Arg80), trehalose biosynthesis (Tps2), and the integrated stress response (Gcn2) in combating proteotoxic insults. We posit that multiple metabolic pathways integrate with classical protein quality control networks to regulate the protein folding environment. Harnessing these metabolic circuits may offer new avenues to modulate proteostasis when needed.