Ubiquitinome profiling identifies USP13-CMAS axis as critical regulator of hair follicular melanogenesis via K48-linked polyubiquitination

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling Pub Date : 2025-08-26 DOI:10.1016/j.cellsig.2025.112090

Yang Chen , Shuaishuai Hu , Sen Wang , Zhiyuan Bao , Jiawei Cai , Bohao Zhao , Xinsheng Wu

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引用次数: 0

Abstract

The ubiquitin-proteasome system critically regulates melanogenesis through post-translational modifications. However, the specific deubiquitination substrates involved in this regulation remain poorly characterized. This study employed multi-omics integration and functional validation to decipher the role of USP13 in melanocyte (MC) biology. Through quantitative melanin assays and apoptosis/proliferation analyses, we established the dual functionality of USP13 in promoting MC pigmentation and survival. Systematic proteome-ubiquitinome analysis of USP13-overexpressing MCs identified 23 high-confidence substrates. Cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) was recognized as a key mediator. Mechanistically, Co-IP studies demonstratedthat USP13 stabilizes CMAS by specifically cleaving its K48-linked polyubiquitin chains, thereby enhancing melanogenic capacity. Furthermore, a novel transcriptional regulatory axis was identified, in which FOXO4 represses USP13 expression through direct promoter interaction, as demonstrated by luciferase reporter and EMSA assays. This study expands the substrate landscape of USP13 but also delineates a novel FOXO4-USP13-CMAS axis coordinating transcriptional and post-translational control of melanin biosynthesis. The results provide new therapeutic targets for pigmentary disorders.

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泛素组分析发现USP13-CMAS轴通过k48关联的多泛素化作用作为毛囊黑色素生成的关键调节因子

泛素-蛋白酶体系统通过翻译后修饰对黑素形成进行关键调控。然而，参与这一调控的特异性去泛素化底物的特征仍然很差。本研究采用多组学整合和功能验证来破译USP13在黑素细胞（MC）生物学中的作用。通过定量黑色素测定和细胞凋亡/增殖分析，我们确定了USP13在促进MC色素沉着和存活方面的双重功能。对过表达usp13的MCs进行系统的蛋白质组-泛素组分析，鉴定出23个高置信度底物。单磷酸胞苷n -乙酰神经氨酸合成酶（CMAS）被认为是一个关键的中介。在机制上，Co-IP研究表明，USP13通过特异性切割其k48连接的多泛素链来稳定CMAS，从而增强黑色素生成能力。此外，研究人员还发现了一个新的转录调控轴，其中FOXO4通过直接启动子相互作用抑制USP13的表达，荧光素酶报告基因和EMSA实验证实了这一点。这项研究扩大了USP13的底物景观，但也描绘了一个新的FOXO4-USP13-CMAS轴协调黑色素生物合成的转录和翻译后控制。结果为色素疾病的治疗提供了新的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular signalling 生物-细胞生物学

CiteScore

8.40

自引率

0.00%

发文量

250

审稿时长

27 days

期刊介绍： Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.