The exoribonuclease Xrn1 is a post-transcriptional negative regulator of autophagy

Macroautophagy/autophagy is a conserved catabolic process that promotes survival during stress. Autophagic dysfunction is associated with pathologies such as cancer and neurodegenerative diseases. Thus, autophagy must be strictly modulated at multiple levels (transcriptional, post-transcriptional, translational and post-translational) to prevent deregulation. Relatively little is known about the post-transcriptional control of autophagy. Here we report that the exoribonuclease Xrn1/XRN1 functions as a negative autophagy factor in the yeast <i>Saccharomyces cerevisiae</i> and in mammalian cells. In yeast, chromosomal deletion of <i>XRN1</i> enhances autophagy and the frequency of autophagosome formation. Loss of Xrn1 results in the upregulation of autophagy-related (<i>ATG</i>) transcripts under nutrient-replete conditions, and this effect is dependent on the ribonuclease activity of Xrn1. Xrn1 expression is regulated by the yeast transcription factor Ash1 in rich conditions. In mammalian cells, siRNA depletion of XRN1 enhances autophagy and the replication of 2 picornaviruses. This work provides insight into the role of the RNA decay factor Xrn1/XRN1 as a post-transcriptional regulator of autophagy.

巨自噬（Macroautophagy，通常简称自噬（autophagy））是一类保守的分解代谢过程，可在应激条件下促进细胞存活。自噬功能异常与癌症、神经退行性疾病等多种病理状态密切相关。因此，必须对自噬在转录、转录后、翻译及翻译后等多个层面进行严格调控，以避免其调控紊乱。目前学界对自噬的转录后调控机制尚缺乏充分了解。本研究发现，外切核糖核酸酶Xrn1/XRN1在酿酒酵母（<i>Saccharomyces cerevisiae</i>）及哺乳动物细胞中均作为自噬的负调控因子发挥作用。在酿酒酵母中，染色体水平的<i>XRN1</i>基因缺失可增强自噬活性与自噬体形成频率。Xrn1缺失会在营养充足的条件下上调自噬相关（<i>ATG</i>）基因的转录本表达，且该效应依赖于Xrn1的核糖核酸酶活性。在营养丰富的环境中，酿酒酵母转录因子Ash1可调控Xrn1的表达水平。在哺乳动物细胞中，通过小干扰RNA（siRNA）敲低XRN1的表达可增强自噬活性，并促进两种小核糖核酸病毒（picornaviruses）的复制。本研究揭示了RNA降解因子Xrn1/XRN1作为自噬转录后调控因子的功能，为相关领域的研究提供了新的见解。