Abstract
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.
Highlights
Selective autophagy requires the autophagy receptor localizing to the target for degradation
These results suggest that endoplasmic reticulum (ER)-phagy is positively regulated by Msn2/4 through activation of the ATG39 promoter and that Msn2/4 themselves are negatively regulated by protein kinase A (PKA)
Expression from the PATG39-GFP reporter was increased by ER stress and nitrogen starvation; their induction was significantly diminished by msn[2] msn[4] double mutations (Fig. 2D,E). These results suggest that during ER stress response and nitrogen starvation, Msn2/4 positively regulate ATG39 expression via its promoter
Summary
Selective autophagy requires the autophagy receptor localizing to the target for degradation. Atg[39] and Atg[40] function as an autophagy receptor for the endoplasmic reticulum (ER)-selective autophagy, referred to as ER-phagy. We find that the cAMPdependent 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. The autophagy receptor localizing to the target organelle is required for recruiting the core autophagy-related proteins that function in the autophagosome formation[3,4,5]. Atg[39] and Atg[40] have been identified as an autophagy receptor specific for ER-phagy[6]. The budding yeast ER consists of two distinct regions, the perinuclear ER and the cortical ER, which are connected by cytoplasmic
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