Role of Autophagy Induced by Pmel17 in the Pathogenesis of Vitiligo

Lijun Sun,1,2 Jingying Sun,1,2 Yangmeng Feng,1,2 Longfei Zhu,3 Huijin Li,4 Cuixiang Xu,1,2 Chunyan Guo1,2 1Shaanxi Provincial Key Laboratory of Infection and Immune Diseases, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, 710068, People’s Republic of China; 2Shaanxi Province Research Center of Cell Immunological Engineering and Technology, Xi’an, Shaanxi, 710068, People’s Republic of China; 3Department of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, People’s Republic of China; 4Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, Shaanxi, 710021, People’s Republic of ChinaCorrespondence: Cuixiang Xu, Shaanxi Provincial Key Laboratory of Infection and Immune Diseases, Shaanxi Provincial People’s Hospital, 256 Youyi Road, Xi’an, Shaanxi, 710068, People’s Republic of China, Email [email protected] Chunyan Guo, Shaanxi Provincial Key Laboratory of Infection and Immune Diseases, Shaanxi Provincial People’s Hospital, 256 Youyi Road, Xi’an, Shaanxi, 710068, People’s Republic of China, Email [email protected]: Vitiligo is a prevalent depigmentation skin disorder with a complex etiology and incompletely understood pathogenesis. Previous studies have suggested a potential involvement of premelanosome protein 17 (Pmel17) in vitiligo, although the specific mechanism remains unclear. This study aimed to explore the association between Pmel17 and vitiligo development, as well as its mechanistic actions.Methods: Initially, clinical samples from vitiligo patients and healthy individuals were collected to assess Pmel17 and tyrosinase (TYR) expression levels in tissues using immunohistochemistry and RT-PCR. Subsequently, the effect of Pmel17 on the vitiligo phenotype was validated in a mouse model. Finally, at the cellular level, Pmel17-siRNA was transfected into melanocytes to evaluate the effect and mechanism of Pmel17 on melanin synthesis.Results: Compared with normal skin tissues, the expressions of TYR and Pmel17 in the lesions of patients with advanced vitiligo was significantly reduced. The results of animal experiments demonstrated that Pmel17-shRNA lentivirus infection induced depigmentation in mice and exacerbated the vitiligo phenotype in monobenzone model mice. At a cellular level, down-regulation of Pmel17 expression reduced melanin synthesis and induced autophagy in melanocytes, concomitant with inhibition of the PI3K-AKT-mTOR signaling pathway. Treatment with LY294002, a PI3K/AKT inhibitor, enhanced the suppressive effects of Pmel17 down-regulation on p-AKT and p-mTOR proteins. Conversely, upregulation of Pmel17 in melanocytes did not impact TYR expression or melanin content.Conclusion: The findings demonstrate that downregulation of Pmel17 contributes to the pathogenesis of vitiligo by inducing autophagy and inhibiting melanin synthesis, through the suppression of the PI3K-AKT-mTOR signaling pathway. These results provide new insights into the molecular mechanism between Pmel17 dysfunction and depigmentation.Keywords: vitiligo, Pmel17, melanin synthesis, autophagy