A systemic cell stress signal confers neuronal resilience toward oxidative stress in a Hedgehog-dependent manner.
A systemic cell stress signal confers neuronal resilience toward oxidative stress in a Hedgehog-dependent manner.
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DOI：
10.1016/j.celrep.2022.111488
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发表时间：
2022-10-18
期刊：
影响因子：
8.8
通讯作者：
Hengst, Ulrich
中科院分区：
文献类型：
--
作者：
Chung, Kyung Min;Kim, Hyunha;Roque, Claudio Gouveia;McCurdy, Ethan P.;Nguyen, Trang T. T.;Siegelin, Markus D.;Huang, Jee-Yeon;Hengst, Ulrich
细胞具有几种保守的适应机制来应对压力。应激信号被启动以重建细胞内稳态，但其对组织或全身水平的影响远未被理解。我们报告说，分泌的内质网（ER）应激转导蛋白CREB3L2（我们命名为TAILS [transmissible activator of increased cell livability under stress]）的管腔域是一种内源性的，细胞非自主的神经元弹性激活剂。作为对氧化损伤的反应，神经元分泌TAILS，其通过与Sonic hedgehog（SHH）及其受体PTCH 1的直接相互作用来增强hedgehog信号传导，从而改善邻近神经元中的抗氧化信号传导和线粒体功能。在缺血性脑损伤的体内模型中，给予TAILS能够使CNS神经元存活，并在行为测试中完全保留认知功能。我们的研究结果揭示了SHH介导的细胞应激信号传导的细胞非自主分支，其赋予成熟脑中对氧化应激的恢复力，提供对缺血性神经变性的保护。人们对神经元是否以及如何将压力传递给其他神经元还知之甚少。Chung等人证明，神经元中的氧化应激导致细胞非自主应激信号蛋白的分泌。这种蛋白质TAILS以SHH依赖的方式诱导受体细胞中神经元对细胞应激的恢复力。
Cells possess several conserved adaptive mechanisms to respond to stress. Stress signaling is initiated to reestablish cellular homeostasis, but its effects on the tissue or systemic levels are far less understood. We report that the secreted luminal domain of the endoplasmic reticulum (ER) stress transducer CREB3L2 (which we name TAILS [transmissible activator of increased cell livability under stress]) is an endogenous, cell non-autonomous activator of neuronal resilience. In response to oxidative insults, neurons secrete TAILS, which potentiates hedgehog signaling through direct interaction with Sonic hedgehog (SHH) and its receptor PTCH1, leading to improved antioxidant signaling and mitochondrial function in neighboring neurons. In an in vivo model of ischemic brain injury, administration of TAILS enables survival of CNS neurons and fully preserves cognitive function in behavioral tests. Our findings reveal an SHH-mediated, cell non-autonomous branch of cellular stress signaling that confers resilience to oxidative stress in the mature brain, providing protection from ischemic neurodegeneration. Whether and how neurons can communicate stress to other neurons is poorly understood. Chung et al. demonstrate that oxidative stress in neurons leads to secretion of cell non-autonomous stress signaling protein. This protein, TAILS, induces neuronal resilience against cell stress in recipient cells in an SHH-dependent manner.
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