Msn2/4 transcription factors positively regulate expression of Atg39 ER-phagy receptor.

Selective autophagy requires the autophagy receptor specifically localizing to the target for degradation. In the budding yeast, Atg39 and Atg40 function as an autophagy receptor for the endoplasmic reticulum (ER)-selective autophagy, referred to as ER-phagy. The expression level of the ATG39 gene is increased in response to ER stress and nitrogen starvation. Under unstressed conditions, ATG39 transcription is repressed by Mig1/2 repressors. ER stress activates Snf1 AMP-activated protein kinase (AMPK), which negatively regulates Mig1/2 and consequently derepresses ATG39 transcription. However, ATG39 expression is still induced by ER stress and nitrogen starvation in the absence of Snf1, suggesting that additional molecules are involved in regulation of ATG39 expression. Here, we identify Msn2/4 transcription factors as an activator of ATG39 transcription. Not only ATG39 promoter activity but also ER-phagy are downregulated by loss of Msn2/4 and disruption of Msn2/4-binding consensus sequences located in the ATG39 promoter. We also find that the cAMP-dependent protein kinase pathway is involved in Msn2/4-mediated transcriptional regulation of ATG39. Our results suggest that yeast ER-phagy is appropriately controlled through modulation of the expression level of the ER-phagy receptor involving multiple signaling pathways and transcription factors.