Abstract
Re-epithelialization is a fundamental process in wound healing that involves various cytokines and cells during cutaneous barrier reconstruction. Ubiquitin-specific peptidase 15 (USP15), an important member of the deubiquitinating enzymes (DUBs), removes ubiquitin chains from target proteins and maintains protein stability. However, the dynamic role of USP15 in epithelialization remains unclear. We aimed to investigate the regulatory function of USP15 in re-epithelialization. An excisional wound splinting model was established to evaluate the re-epithelialization rate in Usp15 knockout (KO) mice. Coimmunoprecipitation (Co-IP) and mass spectrum analyses were performed to identify USP15-interacting proteins. RNA-sequencing was performed for transcriptome analysis in keratinocytes and uploaded into NODE database (http://www.biosino.org/node, accession numbers: OEP000770 and OEP000763). First, a significant delay in epithelialization was observed in the Usp15 KO mice. Moreover, inhibition of cell migration and proliferation was observed in the USP15-silenced keratinocytes (HaCaTs). Moreover, we revealed for the first time that USP15 could interact with eukaryotic initiation factor 4A-1 (EIF4A1), thereby promoting translational efficacy in keratinocytes, which is essential for keratinocyte proliferation and migration. Conclusively, the USP15-EIF4A1 complex significantly accelerated re-epithelialization in wound healing. These observations helped elucidate the function and mechanisms of USP15 in modulating re-epithelialization in wound healing, providing a promising target for refractory wound treatment.
Highlights
MATERIALS AND METHODSWound healing is a complicated biological processes, involving the spatial and temporal synchronization of various cells and cytokines, with a distinct pattern in inflammatory, proliferative and remodeling phases (Tellechea et al, 2019)
We confirmed that the Ubiquitin-specific peptidase 15 (USP15) protein expression in keratinocytes was silenced in the Usp15 knockout mice (Figure 1D, lanes 7–12)
We examined the epithelium gap of the wound model was significantly increased in Usp15 knockout mice (Figure 1G)
Summary
Wound healing is a complicated biological processes, involving the spatial and temporal synchronization of various cells and cytokines, with a distinct pattern in inflammatory, proliferative and remodeling phases (Tellechea et al, 2019). Deficiencies of homeostasis in the local microenvironment, including alterations in local physical forces, oxygen content, chemokines secretion and extracellular matrix remodeling, leads to impaired wound healing (Zhang et al, 2019). Delayed wound healing results in pain, infections, financial expenditures and loss of physical function, which affect over 40 million people (Miura et al, 2019). Mice expressing human S100A2 exhibited delayed cutaneous wound repair, and the p53-S100A2 feedback loop impairs re-epithelialization in wound healing (Pan et al, 2018). Adipose stem cell-derived exosomes combined with hyaluronic acid significantly accelerated wound healing through promoting epithelialization and angiogenesis (Liu et al, 2019)
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