Macronucleophagy maintains cell viability under nitrogen starvation by modulating micronucleophagy.

Lysosome/vacuole-mediated intracellular degradation pathways, collectively known as autophagy, play crucial roles in the maintenance and regulation of various cellular functions. However, little is known about the relationship between different modes of autophagy. In the budding yeast Saccharomyces cerevisiae, nitrogen starvation triggers both macronucleophagy and micronucleophagy, in which nuclear components are degraded via macroautophagy and microautophagy, respectively. We previously revealed that Atg39-mediated macronucleophagy is important for cell survival under nitrogen starvation; however, the underlying mechanism remains unknown. Here, we reveal that defective Atg39-mediated macronucleophagy leads to the hyperactivation of micronucleophagy, resulting in the excessive transport of various nuclear components into the vacuole. Micronucleophagy occurs at the nucleus-vacuole junction (NVJ). We show that nuclear membrane proteins localized to the NVJ, including Nvj1, which is responsible for micronucleophagy, are degraded via macronucleophagy. Therefore, defective Atg39-mediated macronucleophagy results in the accumulation of Nvj1, which contributes to micronucleophagy enhancement. Blocking micronucleophagy almost completely suppresses cell death caused by the absence of Atg39, whereas enhanced micronucleophagy correlates with death in Atg39-mutant cells under nitrogen starvation. These results suggest that macronucleophagy modulates micronucleophagy in order to prevent the excess removal of nuclear components, thereby maintaining nuclear and cellular homeostasis during nitrogen starvation.