Dhh1 promotes autophagy-related protein translation during nitrogen starvation

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.巨自噬（Macroautophagy，以下简称自噬）是一类高度保守的细胞过程，可将细胞质组分运送至液泡/溶酶体中进行降解与回收。已有研究阐明了营养匮乏条件下自噬相关（ATG）基因的转录调控分子机制，但目前对其翻译调控机制却知之甚少。本研究发现，DExD/H盒RNA解旋酶（DExD/H-box RNA helicase）Dhh1对于自噬诱导所必需的两种蛋白——Atg1与Atg13的高效翻译不可或缺。在氮饥饿条件下，Dhh1可直接结合ATG1与ATG13 mRNA；这两种ATG mRNA的起始密码子下游紧邻的结构化区域，是其受Dhh1调控翻译所必需的序列。Dhh1的RNA结合能力与解旋酶活性，均为促进Atg1翻译及自噬过程所必需。此外，真核翻译起始因子4E（EIF4E）结合蛋白1（Eap1）——一种受雷帕霉素靶蛋白（TOR）调控的EIF4E结合蛋白——可在氮饥饿后与Dhh1发生物理互作，并促进Atg1与Atg13的翻译。上述结果提出了一种调控模型，用以阐释部分ATG基因如何规避氮饥饿过程中发生的整体翻译抑制，从而维持自噬的正常水平。