An Autophagy-Independent Role for <i>ATG41</i> in Sulfur Metabolism During Zinc Deficiency

Abstract

The Zap1 transcription factor of <i>Saccharomyces cerevisiae</i> is a key regulator in the genomic responses to zinc deficiency. Among the genes regulated by Zap1 during zinc deficiency is the autophagy-related gene <i>ATG41</i> Here, we report that Atg41 is required for growth in zinc-deficient conditions, but not when zinc is abundant or when other metals are limiting. Consistent with a role for Atg41 in macroautophagy, we show that nutritional zinc deficiency induces autophagy and that mutation of <i>ATG41</i> diminishes that response. Several experiments indicated that the importance of <i>ATG41</i> function to growth during zinc deficiency is not because of its role in macroautophagy, but rather is due to one or more autophagy-independent functions. For example, rapamycin treatment fully induced autophagy in zinc-deficient <i>atg41</i>Δ mutants but failed to improve growth. In addition, <i>atg41</i>Δ mutants showed a far more severe growth defect than any of several other autophagy mutants tested, and <i>atg41</i>Δ mutants showed increased Heat Shock Factor 1 activity, an indicator of protein homeostasis stress, while other autophagy mutants did not. An autophagy-independent function for <i>ATG41</i> in sulfur metabolism during zinc deficiency was suggested by analyzing the transcriptome of <i>atg41</i>Δ mutants during the transition from zinc-replete to -deficient conditions. Analysis of sulfur metabolites confirmed that Atg41 is needed for the normal accumulation of methionine, homocysteine, and cysteine in zinc-deficient cells. Therefore, we conclude that Atg41 plays roles in both macroautophagy and sulfur metabolism during zinc deficiency.