2. Academic Validation
  3. Aberrant phase separation drives membranous organelle remodeling and tumorigenesis

Aberrant phase separation drives membranous organelle remodeling and tumorigenesis

  • Mol Cell. 2025 May 1;85(9):1852-1867.e10. doi: 10.1016/j.molcel.2025.04.001.
Xinyu Wang 1,  Amin Jiang 1,  Quan Meng 2,  Tao Jiang 1,  Huaide Lu 1,  Xiaohan Geng 1,  Zikuo Song 3,  Xinyao Hu 1,  Zhu Yu 2,  Wencong Xu 4,  Chao Ning 1,  Yajing Lin 1,  Dong Li 5
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 2 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, IDG/McGovern Institute for Brain Research, New Cornerstone Science Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 4 Department of Automation, Tsinghua University, Beijing 100084, China.
  • 5 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, IDG/McGovern Institute for Brain Research, New Cornerstone Science Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: li-dong@tsinghua.edu.cn.
PMID: 40273917 DOI: 10.1016/j.molcel.2025.04.001
Abstract

Membrane remodeling is essential for numerous cellular functions. Although liquid-liquid phase separation (LLPS) of intrinsically disordered region (IDR)-rich proteins could drive dramatic membrane remodeling of artificial giant unilamellar vesicles, it remains elusive whether LLPS-mediated membrane-remodeling functions in live cells and what role it plays in specific bioprocesses. Here, we show that three IDR-rich integral transmembrane fusion proteins (MFPs), generated by chromosomal translocations, can lead to de novo remodeling of their located membranous organelles. Taking FUS-CREB3L2, prevalent in low-grade fibromyxoid sarcoma (LGFMS), as a proof of concept, we recorded super-resolution long-time imaging of endoplasmic reticulum (ER) remodeling dynamics as accumulating FUS-CREB3L2, meanwhile causing spontaneous ER stress to hijack the X-box-binding protein 1 (XBP1) pathway. We further reveal the underlying mechanisms of how FUS-CREB3L2 transduces its tumorigenic signals and aberrant LLPS effects from the ER membrane into the nucleus autonomously, which activates hundreds of LGFMS-specific genes de novo compared with CREB3L2, thus sufficiently reprogramming the cells into an LGFMS-like status.

Keywords

ER stress; FUS-CREB3L2; fusion proteins; membrane remodeling; phase separation; spontaneous regulated intramembrane proteolysis.

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