Zinc starvation induces autophagy in yeast

Abstract

Zinc is an essential nutrient for all forms of life. Within cells, most zinc is bound to protein. Because zinc serves as a catalytic or structural cofactor for many proteins, cells must maintain zinc homeostasis under severely zinc-deficient conditions. In yeast, the transcription factor Zap1 controls the expression of genes required for uptake and mobilization of zinc, but to date the fate of existing zinc-binding proteins under zinc starvation remains poorly understood. Autophagy is an evolutionarily conserved cellular degradation/recycling process in which cytoplasmic proteins and organelles are sequestered for degradation in the vacuole/lysosome. In this study, we investigated how autophagy functions under zinc starvation. Zinc depletion induced non-selective autophagy, which is important for zinclimited growth. Induction of autophagy by zinc starvation was not directly related to transcriptional activation of Zap1. Instead, TORC1 inactivation directed zinc starvation-induced autophagy. Abundant zinc proteins, such as Adh1, Fba1, and ribosomal protein Rpl37, were degraded in an autophagy-dependent manner. But the targets of autophagy were not restricted to zinc-binding proteins. When cellular zinc is severely depleted, this non-selective autophagy plays a role in releasing zinc from the degraded proteins and recycling zinc for other essential purposes.

Zinc deficiency: An unexpected trigger for autophagy

“…In mammalian cells, zinc depletion, for example by zinc chelation, causes a significant suppression of autophagy whereas zinc addition stimulates autophagy in human hepatoma cells across several stimuli (3)(4)(5)(6)(7). Although the forecast for other species might be expected to follow this precedent, Kawamata et al (8) now report the unexpected finding that zinc starvation triggers autophagy in yeast. Kawamata et al (8) demonstrate that autophagy is robustly activated upon zinc starvation using zinc-depleted media as shown by two autophagic markers, GFP-atg8 and API.…”

“…The answer was rather surprising: Kawamata et al (8) tested a series of strains with proteins from autophagy pathways knocked out and found that zinc starvation-induced autophagy relies on the essential non-selective autophagy protein ATG2 and key autophagic degradation proteins Pep4/Prb1, but not the selective autophagy proteins ATG11/ATG19. They also observed the accumulation of ribosomes and mitochondria in autophagic vacuoles by electron microscopy.…”

Effect of zinc intake on hepatic autophagy during acute alcohol intoxication

“…The colocalization of zinc with these vesicles found in this study and in a previous report (Lee et al 2009) supports this hypothesis. Interestingly, a recent study showed that zinc depletion induced autophagy in yeast (Kawamata et al 2017). Further studies are needed to determine what causes the differential response to zinc in yeast and mammalian cells.…”

An Autophagy-Independent Role for ATG41 in Sulfur Metabolism During Zinc Deficiency

“…This would allow for a limited supply of zinc to be 590 29 redistributed to sites of higher priority for zinc-deficient growth. Ohsumi and colleagues 591 (KAWAMATA et al 2017) showed that autophagy was induced normally in zinc-deficient zap1Δ 592 mutant cells. These results suggest that the basal level of Atg41 expressed in zap1Δ mutant 593 cells is sufficient to mediate normal autophagy in zinc-deficient cells.…”

“…proteins (KAWAMATA et al 2017). This would allow for a limited supply of zinc to be 590 29 redistributed to sites of higher priority for zinc-deficient growth.…”