Hypodermal responses to protein synthesis inhibition induce systemic developmental arrest and AMPK-dependent survival in Caenorhabditis elegans.
Hypodermal responses to protein synthesis inhibition induce systemic developmental arrest and AMPK-dependent survival in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1007520
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发表时间：
2018-07
期刊：
影响因子：
4.5
通讯作者：
Curran SP
中科院分区：
文献类型：
--
作者：
Dalton HM;Curran SP
在整个生物体中，操纵生物合成能力会阻止生命早期的发育，但可以在发育后增加健康和寿命。在这里，我们证明了这种发育停滞不是疾病，而是一种受调节的生存程序，对细胞性能降低作出反应。我们通过减少核糖体生物合成（rps-11/RPS11 RNAi）、翻译起始（ifg-1/EIF3G突变和egl-45/EIF3A RNAi）或核糖体进展（放线菌酮处理）来抑制蛋白质合成，所有这些都导致在C. elegans发育这种静止状态可以持续数周-超过正常的C。线虫的成年寿命-而且是可逆的，因为动物一旦从蛋白质合成抑制的来源中释放出来，就可以恢复繁殖并过正常的寿命。停滞状态提供对热、氧化和重金属应激暴露的抗性。除了细胞自主反应，减少生物合成能力仅在皮下组织是足以驱动生物体水平的发育停滞和抗应激表型。在细胞对蛋白质合成抑制的非自主反应中，咽泵送减少，这取决于AMPK介导的信号传导。响应于蛋白质合成抑制的咽部泵送减少通过暴露于产生蛋白质合成抑制性异生物质的微生物来重现，这可以机械地减少病原体和毒素的摄入。这些数据定义了蛋白质合成抑制反应中存在的短暂的停滞生存状态，并为在生物合成能力降低的发育后动物中观察到的健康衰老的保守增强提供了进化基础。蛋白质合成是一个必不可少的细胞过程，但在多个物种中，发育后蛋白质合成的减少会导致健康和寿命的改善。为了更好地理解蛋白质合成受损的生理反应，我们描述了一种新的发育停滞状态，这种状态在C. elegans发育被捕动物有多种生存促进表型，都依赖于细胞能量传感器，AMP激酶。这种生存反应通过皮下组织起作用，导致咽部泵血减少，表明动物对感知到的外部威胁做出反应，即使在成年人中也是如此。此外，将动物暴露于病原体或它们产生的异生物质中，可以重现这些表型，为成年人的有益反应如何通过抑制蛋白质合成等基本生物过程而进化提供了潜在的进化解释。
Across organisms, manipulation of biosynthetic capacity arrests development early in life, but can increase health- and lifespan post-developmentally. Here we demonstrate that this developmental arrest is not sickness but rather a regulated survival program responding to reduced cellular performance. We inhibited protein synthesis by reducing ribosome biogenesis (rps-11/RPS11 RNAi), translation initiation (ifg-1/EIF3G mutation and egl-45/EIF3A RNAi), or ribosome progression (cycloheximide treatment), all of which result in a specific arrest at larval stage 2 of C. elegans development. This quiescent state can last for weeks—beyond the normal C. elegans adult lifespan—and is reversible, as animals can resume reproduction and live a normal lifespan once released from the source of protein synthesis inhibition. The arrest state affords resistance to thermal, oxidative, and heavy metal stress exposure. In addition to cell-autonomous responses, reducing biosynthetic capacity only in the hypodermis was sufficient to drive organism-level developmental arrest and stress resistance phenotypes. Among the cell non-autonomous responses to protein synthesis inhibition is reduced pharyngeal pumping that is dependent upon AMPK-mediated signaling. The reduced pharyngeal pumping in response to protein synthesis inhibition is recapitulated by exposure to microbes that generate protein synthesis-inhibiting xenobiotics, which may mechanistically reduce ingestion of pathogen and toxin. These data define the existence of a transient arrest-survival state in response to protein synthesis inhibition and provide an evolutionary foundation for the conserved enhancement of healthy aging observed in post-developmental animals with reduced biosynthetic capacity. Protein synthesis is an essential cellular process, but post-developmental reduction of protein synthesis across multiple species leads to improved health- and lifespan. To better understand the physiological responses to impaired protein synthesis, we characterize a novel developmental arrest state that occurs when reducing protein synthesis during C. elegans development. Arrested animals have multiple survival-promoting phenotypes that are all dependent on the cellular energy sensor, AMP kinase. This survival response acts through the hypodermis and causes a reduction in pharyngeal pumping, indicating that the animal is responding to a perceived external threat, even in adults. Furthermore, exposing animals to pathogens, or xenobiotics they produce, can recapitulate these phenotypes, providing a potential evolutionary explanation for how a beneficial response in adults could evolve through the inhibition of an essential biological process such as protein synthesis.
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