Parkin-Mediated Ubiquitination of DCUN1D1: Implications for CXCL10 Regulation in Vitiligo

Vitiligo is a skin disorder marked by the loss of pigmentation due to melanocyte destruction. Our previous study demonstrated that DCUN1D1 is a novel regulator of CXCL10 and is associated with mitochondrial dysfunction. RNA-seq data revealed that the expression of Parkin, a mitophagy-related molecule, is decreased in vitiligo patients. Parkin functions as an E3 ubiquitin ligase. Based on these findings, we hypothesize that Parkin ubiquitinates DCUN1D1, thereby influencing the level of CXCL10 during the progression of vitiligo. Parkin and DCUN1D1 expression levels were assessed in both vitiligo patients and mice. To examine interactions, HaCaT cells were transfected with Flag-DCUN1D1, Myc-PRKN, or HA-Ub, followed by coimmunoprecipitation (co-IP) and Western blotting analysis. Mitochondrial activity and mitophagy were evaluated following various treatments, including the use of CCCP. HaCaT cells were transfected with DCUN1D1 or different concentrations of Parkin to assess CXCL10 levels. The supernatant from HaCaT cells was collected and incubated with melanocytes for 48 h, after which the apoptosis level was examined. DCUN1D1 was found to be upregulated, whereas Parkin was downregulated in both vitiligo patients and mice. Parkin interacts with DCUN1D1 and ubiquitinates it at lysine 27 (K27). Increased levels of Parkin counteract the reductions in mitochondrial activity and mitophagy induced by DCUN1D1, significantly downregulate CXCL10 levels, and reduce melanocyte apoptosis. This study provides evidence that Parkin-mediated ubiquitination of DCUN1D1 regulates CXCL10 levels in vitiligo, thereby offering a new experimental foundation for understanding the pathogenesis of vitiligo.