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

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

  • Nat Commun. 2025 Aug 4;16(1):7165. doi: 10.1038/s41467-025-62343-3.
Man-Xiu Xie # 1,  Ren-Chun Lai # 1,  Yi-Bin Xiao # 2 3,  Shi-Yu Zuo # 2,  Hao Tang # 1,  Xian-Ying Cao 4,  Jin-Kun Liu 2,  Zi-Su Zhou 3,  Shu-Hang Wang 3,  Xiao-Fan Lu 1,  Ying He 2,  Yan Xie 2,  Xiao-Long Zhang 5
Affiliations

Affiliations

  • 1 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.
  • 2 Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
  • 3 Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou, China.
  • 4 Hainan Vocational University of Science and Technology, Haikou, China.
  • 5 Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China. zhangxiaolong@gdph.org.cn.
  • # Contributed equally.
PMID: 40759894 DOI: 10.1038/s41467-025-62343-3
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.

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