Abstract
Macroautophagy (hereafter autophagy) is a well-conserved cellular process through which cytoplasmic components are delivered to the vacuole/lysosome for degradation and recycling. Studies have revealed the molecular mechanism of transcriptional regulation of autophagy-related (ATG) genes upon nutrient deprivation. However, little is known about their translational regulation. Here, we found that Dhh1, a DExD/H-box RNA helicase, is required for efficient translation of Atg1 and Atg13, two proteins essential for autophagy induction. Dhh1 directly associates with ATG1 and ATG13 mRNAs under nitrogen-starvation conditions. The structured regions shortly after the start codons of the two ATG mRNAs are necessary for their translational regulation by Dhh1. Both the RNA-binding ability and helicase activity of Dhh1 are indispensable to promote Atg1 translation and autophagy. Moreover, eukaryotic translation initiation factor 4E (EIF4E)-associated protein 1 (Eap1), a target of rapamycin (TOR)-regulated EIF4E binding protein, physically interacts with Dhh1 after nitrogen starvation and facilitates the translation of Atg1 and Atg13. These results suggest a model for how some ATG genes bypass the general translational suppression that occurs during nitrogen starvation to maintain a proper level of autophagy.
Highlights
Autophagy is a tightly controlled cellular process by which cytosolic proteins, protein aggregates, damaged or surplus organelles, and invading pathogens are sequestered within a double-membrane vesicle and delivered to the vacuole/lysosome for degradation and recycling [1,2]
There was no processing of phosphoglucoisomerase 1 (Pgi1)–green fluorescent protein (GFP) in the atg1Δ cells that are defective for autophagy, demonstrating that the generation of free GFP was dependent on autophagic degradation of the chimera
In the dhh1Δ cells, a substantially reduced amount of free GFP was detected starting at 1 d after nitrogen starvation compared to the WT cells, suggesting that long-term autophagy was impaired in this mutant (Fig 1C and S1A Fig)
Summary
Autophagy is a tightly controlled cellular process by which cytosolic proteins, protein aggregates, damaged or surplus organelles, and invading pathogens are sequestered within a double-membrane vesicle (the autophagosome) and delivered to the vacuole/lysosome for degradation and recycling [1,2]. Studies in yeasts have identified more than 40 autophagy-related (ATG) genes involved in mediating autophagy [7], and many of the corresponding gene products have homologs or functional counterparts in higher eukaryotes [2]. The expression levels of ATG genes are important for maintaining proper levels of autophagy activity [8,9]. Expression of most ATG genes is up-regulated under autophagy-inducing conditions such as nutrient deprivation [10]. The transcriptional regulation of ATG genes has been extensively investigated, and an increasing number of transcriptional activators and repressors involved in autophagy regulation are being characterized in both yeast and mammals [8,10,11,12,13,14]
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