Scholarlink

<p>The mitochondria-localized deubiquitinase USP30 regulates mitophagy and mitochondrial homeostasis, playing a significant role in the progression of neurodegenerative diseases. However, its role in cancer remains poorly understood. Through metabolism-related gene set enrichment analysis, we identified USP30 as a key modulator of glucose metabolism in cancer cells. Utilizing quantitative proteomic and ubiquitinomic approaches coupled with co-immunoprecipitation assays, we elucidated that USP30 regulates glycolysis by interacting with hexokinase HK1 and HK2, a process dependent on its enzymatic activity. USP30 modulates the ubiquitination profile of HK1 and HK2 by preferentially removing atypical ubiquitin chains, thereby enhancing their stability, mitochondrial localization, VDAC1 binding and hexokinase activity. Lysine 144 emerges as a critical regulatory site for USP30-mediated deubiquitination of HK2. Mutation of K144 enhances HK2 stability, increases its mitochondrial localization and binding to VDAC1, and significantly augments hexokinase activity. Furthermore, the HK2 K144 mutation markedly enhances tumor cell glycolysis, fostering increased proliferation and migration both in vitro and in vivo. These findings underscore USP30 as a novel regulator of glycolysis in cancer cells via modulation of HK2 ubiquitination dynamics, suggesting its potential as a therapeutic target in cancer metabolism.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

USP30-mediated Deubiquitination of Hexokinase 2 controls the metabolic fate of glucose and tumor progression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月14日

查看全文
  • Zhang Haowei,
  • Xiaolin Li,
  • Weijie Liao,
  • Xuan Qin,
  • Yapei Jiang,
  • Haitao Yang,
  • Hongli Zeng,
  • Yuetong Li,
  • Weidong Xie,
  • Yaou Zhang,
  • Naihan Xu

摘要

The mitochondria-localized deubiquitinase USP30 regulates mitophagy and mitochondrial homeostasis, playing a significant role in the progression of neurodegenerative diseases. However, its role in cancer remains poorly understood. Through metabolism-related gene set enrichment analysis, we identified USP30 as a key modulator of glucose metabolism in cancer cells. Utilizing quantitative proteomic and ubiquitinomic approaches coupled with co-immunoprecipitation assays, we elucidated that USP30 regulates glycolysis by interacting with hexokinase HK1 and HK2, a process dependent on its enzymatic activity. USP30 modulates the ubiquitination profile of HK1 and HK2 by preferentially removing atypical ubiquitin chains, thereby enhancing their stability, mitochondrial localization, VDAC1 binding and hexokinase activity. Lysine 144 emerges as a critical regulatory site for USP30-mediated deubiquitination of HK2. Mutation of K144 enhances HK2 stability, increases its mitochondrial localization and binding to VDAC1, and significantly augments hexokinase activity. Furthermore, the HK2 K144 mutation markedly enhances tumor cell glycolysis, fostering increased proliferation and migration both in vitro and in vivo. These findings underscore USP30 as a novel regulator of glycolysis in cancer cells via modulation of HK2 ubiquitination dynamics, suggesting its potential as a therapeutic target in cancer metabolism.