USP25 deubiquitinates cytosolic METTL3 to impede glioma proliferation via an m6A-independent pathway
Year: 2025
Type: article
Abstract: METTL3 exhibits distinct tumorigenic roles in the nucleus and cytoplasm, but whether its post-transcriptional modifications vary by subcellular localization remains unclear. Here, we identify METTL3 as a substrate of the deubiquitinase USP25, which stabilizes cytosolic METTL3 by cleaving its K48-linked polyubiquitin chains, preventing proteasomal degradation, without affecting nuclear METTL3 or global m6A abundance. The analysis of clinical glioma samples reveals a positive correlation between USP25 and METTL3 protein levels, with both significantly upregulated in high-grade glioma. Moreover, USP25 enhances EGFR expression through cytosolic METTL3, driving glioma progression. Our findings highlight that METTL3 undergoes distinct post-translational modifications based on its subcellular localization, providing new insights into the spatial regulation of METTL3 in gliomas.
Source: iScience
Authors: Bingchang Zhang, Wanhong Han, Xin Gao, Wenhua Li, Jianhua Yu, Wujie Zhao, Jiawei He, Xiansheng Qiu, Zhenwei Lu, Liwei Zhou, Yahui Hu, Yuanyuan Xie, Yanyan Geng, Hanwen Lu, Wentao Zhao, Xinwen Liao, Shouren Chen, Xiyao Liu, Sifang Chen, Guowei Tan, Yaya Zhang, Zhanxiang Wang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,240
OpenAlex ID: W4415755548