DB20-1008-R1-Supplemental_info_clean_copy.pdf (1.59 MB)
Dedicator of Cytokinesis 5 Regulates Keratinocyte Function and Promotes Diabetic Wound Healing
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posted on 2021-02-24, 22:26 authored 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 ZhengCutaneous 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.