Cytoskeletal activation of NHE1 regulates mechanosensitive cell volume adaptation and proliferation

Qin Ni; Zhuoxu Ge; Yizeng Li; Gabriel Shatkin; Jinyu Fu; Anindya Sen; Kaustav Bera; Yuhan Yang; Yichen Wang; Yufei Wu; Ana Carina Nogueira Vasconcelos; Yuqing Yan; Dingchang Lin; Andrew P Feinberg; Konstantinos Konstantopoulos; Sean X Sun

doi:10.1016/j.celrep.2024.114992

Cytoskeletal activation of NHE1 regulates mechanosensitive cell volume adaptation and proliferation

Cell Rep. 2024 Nov 22;43(12):114992. doi: 10.1016/j.celrep.2024.114992. Online ahead of print.

Authors

Qin Ni¹, Zhuoxu Ge¹, Yizeng Li², Gabriel Shatkin³, Jinyu Fu⁴, Anindya Sen⁵, Kaustav Bera⁵, Yuhan Yang⁶, Yichen Wang⁷, Yufei Wu¹, Ana Carina Nogueira Vasconcelos¹, Yuqing Yan⁸, Dingchang Lin⁸, Andrew P Feinberg⁹, Konstantinos Konstantopoulos¹⁰, Sean X Sun¹¹

Affiliations

¹ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA.
² Department of Biomedical Engineering, Binghamton University, Binghamton, NY, USA.
³ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁴ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Physics, Johns Hopkins University, Baltimore, MD, USA.
⁵ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁶ Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁸ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA. Electronic address: ssun@jhu.edu.

PMID: 39579355
DOI: 10.1016/j.celrep.2024.114992

Abstract

Mammalian cells rapidly respond to environmental changes by altering transmembrane water and ion fluxes, changing cell volume. Contractile forces generated by actomyosin have been proposed to mechanically regulate cell volume. However, our findings reveal a different mechanism in adherent cells, where elevated actomyosin activity increases cell volume in normal-like cells (NIH 3T3 and others) through interaction with the sodium-hydrogen exchanger isoform 1 (NHE1). This leads to a slow secondary volume increase (SVI) following the initial regulatory volume decrease during hypotonic shock. The active cell response is further confirmed by intracellular alkalinization during mechanical stretch. Moreover, cytoskeletal activation of NHE1 during SVI deforms the nucleus, causing immediate transcriptomic changes and ERK-dependent growth inhibition. Notably, SVI and its associated changes are absent in many cancer cell lines or cells on compliant substrates with reduced actomyosin activity. Thus, actomyosin acts as a sensory element rather than a force generator during adaptation to environmental challenges.

Keywords: CP: Cell biology; ERK/MAPK; NHE1; PI3K; RNA-seq; cell volume; cytoskeleton; epigenome; math model; mechanosensation; nucleus volume.