Dual purine starvation triggers an Iml1-Whi2-dependent autophagy pathway for survival in yeast

Purines, like amino acids, are fundamental nutrients and essential nucleotide components. ATP and GTP are generated via de novo purine biosynthesis or the salvage pathway. Yeast ADE2 encodes a key de novo pathway enzyme; ade2 mutants accumulate red pigment in vacuoles at late growth stages in rich medium - a phenotype suppressible by exogenous purines. Disruption of purine synthesis induces autophagy in mammalian cells, but whether and how purine starvation triggers autophagy in yeast remains unknown. Here we show that yeast purine biosynthesis mutants experience dual purine starvation - intrinsic purine nucleotide synthesis defect coupled with extracellular purine base exhaustion - during prolonged culture in rich medium. This induces multiple autophagy pathways, including selective ERphagy and mitophagy, non-selective macroautophagy/autophagy, and both selective and non-selective modes of prApe1 maturation, suppressible by certain purine supplementation or ADE2 complementation. Autophagy initiates earlier in mutants, with accelerated dephosphorylation of TORC1 substrates Rps6 and Atg13. Iml1 and Whi2 synergistically transduce the adenine starvation signal and are essential for ERphagy. Functionally, induced autophagy confers resistance to acute adenine starvation and maintains genetic stability via total, but not specific, autophagic activity. These findings link purine status to autophagy, identify Iml1 and Whi2 as key mediators, and offer therapeutic insights for purine-related diseases.