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

Man-Xiu Xie, Ren-Chun Lai, Yi-Bin Xiao, Shi-Yu Zuo, Hao Tang, Xian-Ying Cao, Jin-Kun Liu, Zi-Su Zhou, Shu-Hang Wang, Xiao-Fan Lu, Ying He, Yan Xie and Xiao-Long Zhang ()
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Man-Xiu Xie: Guangdong Provincial Clinical Research Center for Cancer
Ren-Chun Lai: Guangdong Provincial Clinical Research Center for Cancer
Yi-Bin Xiao: Southern Medical University
Shi-Yu Zuo: Southern Medical University
Hao Tang: Guangdong Provincial Clinical Research Center for Cancer
Xian-Ying Cao: Hainan Vocational University of Science and Technology
Jin-Kun Liu: Southern Medical University
Zi-Su Zhou: Zhongshan School of Medicine of Sun Yat-sen University
Shu-Hang Wang: Zhongshan School of Medicine of Sun Yat-sen University
Xiao-Fan Lu: Guangdong Provincial Clinical Research Center for Cancer
Ying He: Southern Medical University
Yan Xie: Southern Medical University
Xiao-Long Zhang: Southern Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62343-3

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