Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089.
Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089.
Proc Natl Acad Sci U S A. 2023 Dec 26;120(52):e2308565120. doi: 10.1073/pnas.2308565120. Epub 2023 Dec 19.
Coordination of cellular responses to stress is essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here, we identify how SKN-1 activation in two ciliated ASI neurons in results in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of noncoding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a unique regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase, , in the intestine, can oppose the effects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell nonautonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.
细胞对应激反应的协调对于整个生命周期的健康至关重要。转录因子 SKN-1 是一种必需的同型平衡因子，可介导应激诱导环境和细胞功能障碍中的存活，但 SKN-1 的组成性激活会导致过早衰老，从而揭示了关闭细胞保护途径的重要性。在这里，我们确定了 中两个有纤毛的 ASI 神经元中的 SKN-1 激活如何导致生物体转录能力的增加，从而导致外周组织的多种表型结果。除了几种非编码 RNA 类别的表达增加外，ASI 神经元中既定的 SKN-1 应激反应和脂质代谢基因类别的 RNA 表达增加定义了具有组成性 SKN-1 激活和健康寿命缩短的动物的分子特征。我们揭示了泛素化作为 SKN-1 同型平衡的独特调节剂，介导肠细胞内 SKN-1 的丰度。此外，在肠道中，dicer 相关 DExD/H-box 解旋酶 的 RNAi 独立活性可以对抗异常 SKN-1 转录激活的影响，并延迟与年龄相关的健康下降。总之，我们的研究结果揭示了一种细胞非自主回路，以响应感觉神经系统中过度的 SKN-1 转录活性来维持机体水平的同型平衡。
