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Cells recognize osmotic stress through liquid–liquid phase separation lubricated with poly(ADP-ribose)

Author

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  • Kengo Watanabe

    (The University of Tokyo)

  • Kazuhiro Morishita

    (The University of Tokyo)

  • Xiangyu Zhou

    (The University of Tokyo)

  • Shigeru Shiizaki

    (The University of Tokyo)

  • Yasuo Uchiyama

    (Juntendo University Graduate School of Medicine)

  • Masato Koike

    (Juntendo University Graduate School of Medicine)

  • Isao Naguro

    (The University of Tokyo)

  • Hidenori Ichijo

    (The University of Tokyo)

Abstract

Cells are under threat of osmotic perturbation; cell volume maintenance is critical in cerebral edema, inflammation and aging, in which prominent changes in intracellular or extracellular osmolality emerge. After osmotic stress-enforced cell swelling or shrinkage, the cells regulate intracellular osmolality to recover their volume. However, the mechanisms recognizing osmotic stress remain obscured. We previously clarified that apoptosis signal-regulating kinase 3 (ASK3) bidirectionally responds to osmotic stress and regulates cell volume recovery. Here, we show that macromolecular crowding induces liquid-demixing condensates of ASK3 under hyperosmotic stress, which transduce osmosensing signal into ASK3 inactivation. A genome-wide small interfering RNA (siRNA) screen identifies an ASK3 inactivation regulator, nicotinamide phosphoribosyltransferase (NAMPT), related to poly(ADP-ribose) signaling. Furthermore, we clarify that poly(ADP-ribose) keeps ASK3 condensates in the liquid phase and enables ASK3 to become inactivated under hyperosmotic stress. Our findings demonstrate that cells rationally incorporate physicochemical phase separation into their osmosensing systems.

Suggested Citation

  • Kengo Watanabe & Kazuhiro Morishita & Xiangyu Zhou & Shigeru Shiizaki & Yasuo Uchiyama & Masato Koike & Isao Naguro & Hidenori Ichijo, 2021. "Cells recognize osmotic stress through liquid–liquid phase separation lubricated with poly(ADP-ribose)," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21614-5
    DOI: 10.1038/s41467-021-21614-5
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    Cited by:

    1. Xin Li & Sheng Wang & Ying Xie & Hongmei Jiang & Jing Guo & Yixuan Wang & Ziyi Peng & Meilin Hu & Mengqi Wang & Jingya Wang & Qian Li & Yafei Wang & Zhiqiang Liu, 2023. "Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Daniel C. Carrettiero & Maria C. Almeida & Andrew P. Longhini & Jennifer N. Rauch & Dasol Han & Xuemei Zhang & Saeed Najafi & Jason E. Gestwicki & Kenneth S. Kosik, 2022. "Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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