USP15 Enhances Re-epithelialization Through Deubiquitinating EIF4A1 During Cutaneous Wound Repair

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.

[Retracted] Platelet‐Rich Plasma‐Derived Exosomal USP15 Promotes Cutaneous Wound Healing via Deubiquitinating EIF4A1

“…In prior studies, USP15 was shown to interact with EIF4A1 and to thereby accelerate wound healing [ 33 ]. Consistent with such a model, we found that USP15 knockdown was sufficient to reduce EIF4A1 expression, while EIF4A1 knockdown directly impaired HaCaT cell migration and proliferation.…”

Platelet Rich Plasma-Derived Exosomal USP15 Promotes Cutaneous Wound Healing via Deubiquitinating EIF4A1

“…In prior studies, USP15 was shown to interact with EIF4A1 and to thereby accelerate wound healing. 30 Consistent with such a model, we found that USP15 knockdown was su cient to reduce EIF4A1 expression, while EIF4A1 knockdown directly impaired HaCaT cell migration and proliferation. Together, these results suggest that the USP15-EIF4A1 axis is a key mediator of the re-epithelialization process.…”

Positive feedback regulation between USP15 and ERK2 inhibits osteoarthritis progression through TGF-β/SMAD2 signaling

“…Consistent with the in vivo or in vitro measurements, we observed that USP15 stimulated the TGF-β signaling pathway through p-SMAD2 and inhibited OA progression by increasing Col2a1, Aggrecan, and Sox9 levels and suppressing Col10a1 and MMP13 levels. According to these reports, USP15 played indispensable roles in many diseases such as safeguarding genome integrity in leukemia cells, promoting the apoptosis of degenerative nucleus pulposus cells, and enhancing re-epithelialization through deubiquitinating EIF4A1 during cutaneous wound repair [40][41][42]. However, there are few previous studies on the effects of USP15 on OA.…”