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

Kengo Watanabe (), Kazuhiro Morishita, Xiangyu Zhou, Shigeru Shiizaki, Yasuo Uchiyama, Masato Koike, Isao Naguro and Hidenori Ichijo ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21614-5

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