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组蛋白乳酰化调节DOCK4以控制热痛觉，并支持动力蛋白介导的Nav1.7转运。

Histone lactylation regulates DOCK4 to control heat nociception and supports Dynein-mediated Nav1.7 trafficking.

作者信息

Xie Man-Xiu, Lai Ren-Chun, Xiao Yi-Bin, Zuo Shi-Yu, Tang Hao, Cao Xian-Ying, Liu Jin-Kun, Zhou Zi-Su, Wang Shu-Hang, Lu Xiao-Fan, He Ying, Xie Yan, Zhang Xiao-Long

机构信息

Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.

Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.

出版信息

Nat Commun. 2025 Aug 4;16(1):7165. doi: 10.1038/s41467-025-62343-3.

DOI:10.1038/s41467-025-62343-3
PMID:40759894
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12322138/
Abstract

Heat nociception involves thermosensors like transient receptor potential channel V1 in dorsal root ganglion (DRG) neurons, but their loss only partially impairs heat sensing, suggesting other mechanisms. Autism frequently involves abnormal pain perception, but its mechanisms remain unclear. Here we show that dedicator of cytokinesis 4 (Dock4), an autism susceptibility gene, is decreased in DRG neurons across multiple pain models via histone H4K8 lactylation. DOCK4 deficiency in sensory neurons increases heat nociception in mice. Mechanistically, DOCK4 interacts with sodium channel Nav1.7 and mediates its trafficking from the membrane to the cytoplasm in DRG neurons. Acting an adaptor protein, DOCK4 binds the motor protein Dynein to form a Dynein/DOCK4/Nav1.7 complex, where Dynein provides the mechanical force for Nav1.7 trafficking. DOCK4 knockdown in sensory neurons also enhances heat nociception in male nonhuman primates. Thus, the Dynein/DOCK4/Nav1.7 complex represents a thermosensor-independent mechanism regulating heat nociception and provides insights into abnormal pain in autism.

摘要

热痛觉感受涉及背根神经节（DRG）神经元中的瞬时受体电位通道V1等温度传感器，但这些传感器的缺失仅部分损害热感觉，这表明存在其他机制。自闭症常涉及异常的疼痛感知，但其机制尚不清楚。在这里，我们表明，作为一种自闭症易感基因的细胞分裂素4（Dock4）在多种疼痛模型的DRG神经元中通过组蛋白H4K8乳酸化而减少。感觉神经元中DOCK4的缺乏会增加小鼠的热痛觉感受。从机制上讲，DOCK4与钠通道Nav1.7相互作用，并介导其在DRG神经元中从膜向细胞质的转运。作为衔接蛋白，DOCK4与动力蛋白结合形成动力蛋白/DOCK4/Nav1.7复合物，其中动力蛋白为Nav1.7的转运提供机械力。感觉神经元中DOCK4的敲低也会增强雄性非人类灵长类动物的热痛觉感受。因此，动力蛋白/DOCK4/Nav1.7复合物代表了一种不依赖温度传感器的调节热痛觉感受的机制，并为自闭症中的异常疼痛提供了见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/23769aae10a0/41467_2025_62343_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/83d21eda5a90/41467_2025_62343_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/4bdd7328d196/41467_2025_62343_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/6af4151f353a/41467_2025_62343_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/0806872a9bf6/41467_2025_62343_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/58eeb80e0da3/41467_2025_62343_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/c79e63b2f434/41467_2025_62343_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/fbd8716a4a93/41467_2025_62343_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/23769aae10a0/41467_2025_62343_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/83d21eda5a90/41467_2025_62343_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/4bdd7328d196/41467_2025_62343_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/6af4151f353a/41467_2025_62343_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/0806872a9bf6/41467_2025_62343_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/58eeb80e0da3/41467_2025_62343_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/c79e63b2f434/41467_2025_62343_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/fbd8716a4a93/41467_2025_62343_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0934/12322138/23769aae10a0/41467_2025_62343_Fig8_HTML.jpg

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