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Dedicator of Cytokinesis 5 Regulates Keratinocyte Function and Promotes Diabetic Wound Healing

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posted on 24.02.2021, 22:26 by Hua Qu, Tian Miao, Yuren Wang, Liang Tan, Bangliang Huang, Linlin Zhang, Xiufei Liu, Min Long, Rui Zhang, Xiaoyu Liao, Xiaoli Gong, Ju Wang, Xin Xiong, Junli Liu, Xi Li, Jiang Yu, Gangyi Yang, Zhiming Zhu, Hongting Zheng, Yi Zheng
Cutaneous wound healing is a fundamental biological and coordinated process, and failure to maintain this process contributes to the dysfunction of tissue homeostasis, increasing the global burden of diabetic foot ulcerations. However, the factors that mediate this process are not fully understood. Here, we identify dedicator of cytokinesis 5 (Dock5) a pivotal role in keratinocyte functions contributing to the process of skin wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte adhesion, migration and proliferation, and influences the functions of extracellular matrix (ECM) deposition by facilitating the ubiquitination of transcription factor ZEB1 to activate laminin-332/integrin signaling. Genetic ablation of Dock5 in mice leads to attenuated re-epithelialization and granulation tissue formation, while Dock5 overexpression-improved skin repair can be abrogated by LAMA3 knockdown. Importantly, Dock5 expression in the skin edge is reduced in patients and animal models of diabetes, further suggesting a direct correlation between its abundance and healing capability. The rescue of Dock5 expression in diabetic mice causes a significant improvement in re-epithelialization, collagen deposition, ECM production and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.

Funding

This work was supported by the National Science Fund for Distinguished Young Scholars (No. 81925007), the National Natural Science Foundation of China (No. 82000769, No. 82070881, No. 82070836, No. 81700714, No.81721001, and No. 81970752), “Talent Project” of Army Medical University (2017R013, 2019R047 and 2019XQYYYJ003-2), and Chongqing Science and Health Joint Medical Research Project (QNXM009).

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