线虫全基因组筛选细胞自噬活性调控基因
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摘要
细胞自噬是一种从酵母到哺乳动物细胞在进化上高度保守的基于溶酶体调节的降解过程。这种独特的生物学过程通常依次分为以下几个步骤：隔离膜的形成(又称为细胞自噬的起始或者细胞自噬前体结构的形成)、细胞自噬小体膜的成核和延伸直至完整自噬小体的形成、细胞自噬小体的成熟、细胞自噬溶酶体的降解以及降解产物的循环再利用。细胞自噬能够有效清除冗余的细胞质成分或损伤的细胞器,因而在细胞胞内蛋白质和细胞器的质量控制中发挥举足轻重的作用。细胞自噬的缺陷将导致胞内异常蛋白聚集体的累积,这些累积的蛋白聚集体可能损坏细胞或有机体的正常生理功能。因此,各种各样的人类疾病都与细胞自噬密切相关,尤其是神经退行性疾病,比如亨廷顿症和阿尔兹海默症。细胞自噬能够被许多种胁迫刺激所激活,比如营养饥饿、能量缺失、活性氧类物质的累积等等。迄今为止,研究发现了许多种可以调节细胞自噬活性的信号转导通路,如mTOR信号通路、Ras/PKA信号通路、胰岛素/类胰岛素样生长因子信号通路和AMPK信号通路。
虽然目前发现了许多可以调节细胞自噬活性的因子,但对于多细胞生物有机体发育过程中细胞自噬的调节和发育信号转导通路是如何协调的相关机制尚不清楚。在本篇论文中,研究发现核糖体大亚基蛋白RPL-43的功能缺失会导致SQST-1(哺乳动物细胞p62同源物)蛋白聚集体在线虫肠道细胞中的累积。这些累积的蛋白聚集体能够被上调的细胞自噬活性有效降解清除。所以以此为模型,本研究进行了线虫全基因组范围RNAi饲养筛选,试图寻找那些功能缺失后能够上调细胞自噬活性的基因。经过几轮反复的确认,最终发现了139个基因在被RNAi干扰掉的情况下能够有效地上调细胞自噬活性从而促进rpl-43突变体中累积的SQST-1蛋白聚集体的降解。进一步的研究工作发现许多发育信号转导通路,包括Sma/Mab TGF-β信号通路、LIN-35/Rb信号通路、XBP-1调节的内质网应激信号通路以及ATFS-1调节的线粒体应激信号通路能够在转录水平调控细胞自噬基因的表达。
之前人们对于细胞自噬的调控的了解都来自体外的细胞生物学研究工作,而体外的研究在许多时候并不能反映体内的真实情况。本研究工作以经典的多细胞模式生物—线虫的遗传突变体rpl-43为模型,筛选获得了许多细胞自噬活性调控基因,并发现了各种信号转导通路可以通过转录水平调节细胞自噬活性。因此,本研究对于人们深入理解各种信号转导通路在生理条件下如何调节细胞自噬活性具有重要意义。
Autophagy is an evolutionarily conserved lysosome-mediated degradation process from yeast to mammals. This unique biological process is always divided into several sequential steps:Isolation membrane formation (initiation or PAS formation), membrane nucleation and expansion until complete autophagosome formation, autophagosome maturation, auto-lysosomal degradation and utilization of degradation products. Autophagy plays a very important role in protein or organelle quality control by eliminating unneeded cytoplasmic contents or damaged organelles. Defective autophagy will cause accumulation of ectopic protein aggregates which may disrupt the normal physiological function of the cells or organisms. Thus, defective autophagy is linked with all kinds of human diseases, especially neuron-neurodegenerative diseases such as Huntington's or Alzheimer's diseases. Autophagy can be activated by many kinds of stress, including nutrient starvation, energy deprivation, reactive oxygen species and so on. Up to now, multiple signaling pathways have been suggested be involved in regulation of autophagy activity, such as mTOR pathway, Ras/PKA pathway, Insulin/IGF-1signaling pathway and AMPK pathway.
Although numerous factors have been uncovered that regulate autophagy activity, the mechanisms which coordinate regulation of autophagy with developmental signaling during multicellular organism development remain largely unknown. In this study, we showed that impaired function of ribosomal protein RPL-43causes accumulation of SQST-1(homolog of mammalian p62) aggregates in the larval intestine and these aggregates are removed upon autophagy induction. So basing on this model, we perform genome-wide RNAi screen to find those genes inactivation of which can up-regulate autophagy activity. After several rounds of confirmation, finally we identified139genes which, when inactivated, effectively up-regulate autophagy activity and thus promote degradation of SQST-1aggregates in rpl-43mutant. Further studies demonstrated that a variety of developmental signaling pathways, including Sma/Mab TGF-β signaling, LIN-35/Rb signaling, the XBP-1-mediated ER stress response and the ATFS-1-mediated mitochondrial stress response, transcriptionally regulate the expression of autophagy genes.
People's understanding of autophagy regulation all comes from cell biology studies in vitro in the past. However, in vitro studies always are not the truth. This study used rpl-43mutant from the classical model organism—C. elegans to perform RNAi screen and found many genes involved in autophagy regulation. Further studies suggested that different signaling pathways can mediate autophagy activity on transcriptional level. Therefore, this study has great significance for people to understand the role of signaling pathways in regulation of autophagy under physiological conditions.
虽然目前发现了许多可以调节细胞自噬活性的因子,但对于多细胞生物有机体发育过程中细胞自噬的调节和发育信号转导通路是如何协调的相关机制尚不清楚。在本篇论文中,研究发现核糖体大亚基蛋白RPL-43的功能缺失会导致SQST-1(哺乳动物细胞p62同源物)蛋白聚集体在线虫肠道细胞中的累积。这些累积的蛋白聚集体能够被上调的细胞自噬活性有效降解清除。所以以此为模型,本研究进行了线虫全基因组范围RNAi饲养筛选,试图寻找那些功能缺失后能够上调细胞自噬活性的基因。经过几轮反复的确认,最终发现了139个基因在被RNAi干扰掉的情况下能够有效地上调细胞自噬活性从而促进rpl-43突变体中累积的SQST-1蛋白聚集体的降解。进一步的研究工作发现许多发育信号转导通路,包括Sma/Mab TGF-β信号通路、LIN-35/Rb信号通路、XBP-1调节的内质网应激信号通路以及ATFS-1调节的线粒体应激信号通路能够在转录水平调控细胞自噬基因的表达。
之前人们对于细胞自噬的调控的了解都来自体外的细胞生物学研究工作,而体外的研究在许多时候并不能反映体内的真实情况。本研究工作以经典的多细胞模式生物—线虫的遗传突变体rpl-43为模型,筛选获得了许多细胞自噬活性调控基因,并发现了各种信号转导通路可以通过转录水平调节细胞自噬活性。因此,本研究对于人们深入理解各种信号转导通路在生理条件下如何调节细胞自噬活性具有重要意义。
Autophagy is an evolutionarily conserved lysosome-mediated degradation process from yeast to mammals. This unique biological process is always divided into several sequential steps:Isolation membrane formation (initiation or PAS formation), membrane nucleation and expansion until complete autophagosome formation, autophagosome maturation, auto-lysosomal degradation and utilization of degradation products. Autophagy plays a very important role in protein or organelle quality control by eliminating unneeded cytoplasmic contents or damaged organelles. Defective autophagy will cause accumulation of ectopic protein aggregates which may disrupt the normal physiological function of the cells or organisms. Thus, defective autophagy is linked with all kinds of human diseases, especially neuron-neurodegenerative diseases such as Huntington's or Alzheimer's diseases. Autophagy can be activated by many kinds of stress, including nutrient starvation, energy deprivation, reactive oxygen species and so on. Up to now, multiple signaling pathways have been suggested be involved in regulation of autophagy activity, such as mTOR pathway, Ras/PKA pathway, Insulin/IGF-1signaling pathway and AMPK pathway.
Although numerous factors have been uncovered that regulate autophagy activity, the mechanisms which coordinate regulation of autophagy with developmental signaling during multicellular organism development remain largely unknown. In this study, we showed that impaired function of ribosomal protein RPL-43causes accumulation of SQST-1(homolog of mammalian p62) aggregates in the larval intestine and these aggregates are removed upon autophagy induction. So basing on this model, we perform genome-wide RNAi screen to find those genes inactivation of which can up-regulate autophagy activity. After several rounds of confirmation, finally we identified139genes which, when inactivated, effectively up-regulate autophagy activity and thus promote degradation of SQST-1aggregates in rpl-43mutant. Further studies demonstrated that a variety of developmental signaling pathways, including Sma/Mab TGF-β signaling, LIN-35/Rb signaling, the XBP-1-mediated ER stress response and the ATFS-1-mediated mitochondrial stress response, transcriptionally regulate the expression of autophagy genes.
People's understanding of autophagy regulation all comes from cell biology studies in vitro in the past. However, in vitro studies always are not the truth. This study used rpl-43mutant from the classical model organism—C. elegans to perform RNAi screen and found many genes involved in autophagy regulation. Further studies suggested that different signaling pathways can mediate autophagy activity on transcriptional level. Therefore, this study has great significance for people to understand the role of signaling pathways in regulation of autophagy under physiological conditions.
引文
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