ATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking.
ATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking.
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ATF4 选择性调节热伤害感受并促进驱动蛋白介导的 TRPM3 运输
DOI：
10.1038/s41467-021-21731-1
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发表时间：
2021-03-03
影响因子：
16.6
通讯作者：
Zhang XL
中科院分区：
文献类型：
--
作者：
Xie MX;Cao XY;Zeng WA;Lai RC;Guo L;Wang JC;Xiao YB;Zhang X;Chen D;Liu XG;Zhang XL
缺乏对患有热过敏症的患者的有效治疗，主要是由于我们对这种疾病的致病机制的了解有限。在神经系统中，转录激活因子4（ATF 4）参与调节突触可塑性和记忆形成。在这里，我们表明ATF 4在热伤害感受中起着重要作用。事实上，小鼠背根神经节（DRG）神经元中ATF 4的缺失选择性地损害热敏感性。从机制上讲，我们发现ATF 4与瞬时受体电位阳离子通道亚家族M成员3（TRPM 3）相互作用，并介导TRPM 3在DRG神经元中对热的反应。ATF 4的缺失也显著降低了电流和KIF 17介导的TRPM 3的运输，表明KIF 17/ATF 4/TRPM 3复合物是神经元对热刺激的反应所必需的。我们的研究结果揭示了ATF 4在DRG神经元对热刺激的反应中的非转录作用。介导伤害感受的分子机制尚不清楚。在这里，作者表明激活转录因子4（ATF 4）对小鼠对热伤害的反应很重要，ATF 4在介导背根神经节神经元中的蛋白质运输中起作用。
Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons. The molecular mechanisms mediating nociception are unclear. Here, the authors show that the Activating Transcription Factor 4 (ATF4) is important for the response to heat nociception in mice and ATF4 role in mediating protein trafficking in dorsal root ganglion neurons.
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