Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS Biol. 2020 Dec 2;18(12):e3000996. doi: 10.1371/journal.pbio.3000996. eCollection 2020 Dec.
RNA interference (RNAi) is an antiviral pathway common to many eukaryotes that detects and cleaves foreign nucleic acids. In mammals, mitochondrially localized proteins such as mitochondrial antiviral signaling (MAVS), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) mediate antiviral responses. Here, we report that mitochondrial dysfunction in Caenorhabditis elegans activates RNAi-directed silencing via induction of a pathway homologous to the mammalian RIG-I helicase viral response pathway. The induction of RNAi also requires the conserved RNA decapping enzyme EOL-1/DXO. The transcriptional induction of eol-1 requires DRH-1 as well as the mitochondrial unfolded protein response (UPRmt). Upon mitochondrial dysfunction, EOL-1 is concentrated into foci that depend on the transcription of mitochondrial RNAs that may form double-stranded RNA (dsRNA), as has been observed in mammalian antiviral responses. Enhanced RNAi triggered by mitochondrial dysfunction is necessary for the increase in longevity that is induced by mitochondrial dysfunction.
RNA 干扰 (RNAi) 是一种普遍存在于许多真核生物中的抗病毒途径，可检测和切割外来核酸。在哺乳动物中，定位于线粒体的蛋白质，如线粒体抗病毒信号 (MAVS)、视黄酸诱导基因 I (RIG-I) 和黑色素瘤分化相关蛋白 5 (MDA5)，介导抗病毒反应。在这里，我们报告说，秀丽隐杆线虫中的线粒体功能障碍通过诱导与哺乳动物 RIG-I 解旋酶病毒反应途径同源的途径，激活 RNAi 介导的沉默。RNAi 的诱导还需要保守的 RNA 去帽酶 EOL-1/DXO。eol-1 的转录诱导需要 DRH-1 以及线粒体未折叠蛋白反应 (UPRmt)。在线粒体功能障碍时，EOL-1 集中在依赖于可能形成双链 RNA (dsRNA) 的线粒体 RNA 转录的焦点中，这在哺乳动物抗病毒反应中已经观察到。线粒体功能障碍引发的增强的 RNAi 对于线粒体功能障碍诱导的寿命延长是必要的。
