Differentially expressed genes in hsp-90neuro.

Organismal proteostasis is maintained by intercellular signaling processes including cell nonautonomous stress responses such as transcellular chaperone signaling (TCS). When TCS is activated upon tissue-specific knockdown of hsp-90 in the Caenorhabditis elegans intestine, heat-inducible hsp-70 is induced in muscle cells at the permissive temperature resulting in increased heat stress resistance and lifespan extension. However, our understanding of the molecular mechanism and signaling factors mediating transcellular activation of hsp-70 expression from one tissue to another is still in its infancy. Here, we conducted a combinatorial approach using transcriptome RNA-Seq profiling and a forward genetic mutagenesis screen to elucidate how stress signaling from the intestine to the muscle is regulated. We find that the TCS-mediated “gut-to-muscle” induction of hsp-70 expression is suppressed by HSF-1 and instead relies on transcellular-X-cross-tissue (txt) genes. We identify a key role for the PDZ-domain guanylate cyclase txt-1 and the homeobox transcription factor ceh-58 as signaling hubs in the stress receiving muscle cells to initiate hsp-70 expression and facilitate TCS-mediated heat stress resistance and lifespan extension. Our results provide a new view on cell-nonautonomous regulation of “inter-tissue” stress responses in an organism that highlight a key role for the gut. Our data suggest that the HSF-1–mediated heat shock response is switched off upon TCS activation, in favor of an intercellular stress-signaling route to safeguard survival.

机体蛋白质稳态（proteostasis）由细胞间信号传导过程维持，其中包括跨细胞伴侣蛋白信号通路（transcellular chaperone signaling, TCS）这类细胞非自主性应激反应。当在秀丽隐杆线虫（Caenorhabditis elegans）肠道内进行组织特异性的hsp-90敲低以激活TCS后，在容许温度下，肌肉细胞中会诱导出热诱导型hsp-70，进而提升热应激抗性并延长寿命。然而，目前学界对介导跨组织激活hsp-70表达的分子机制与信号因子的认知仍较为有限。本研究通过转录组RNA测序分析与正向遗传诱变筛选的组合策略，阐明了肠道向肌肉传递的应激信号的调控机制。我们发现，TCS介导的“肠-肌肉”hsp-70表达诱导过程会被热休克因子1（HSF-1）抑制，且该过程依赖于跨组织-X-跨组织（transcellular-X-cross-tissue, txt）基因家族。我们鉴定出PDZ结构域鸟苷酸环化酶txt-1与同源盒转录因子ceh-58作为应激接收肌肉细胞中的信号枢纽，可启动hsp-70表达并促进TCS介导的热应激抗性与寿命延长。本研究为生物体“组织间”应激反应的细胞非自主性调控提供了新视角，凸显了肠道的关键作用。我们的数据表明，在TCS激活后，HSF-1介导的热休克反应会被关闭，转而启用细胞间应激信号通路以保障机体存活。