2. Academic Validation
  3. Sensing plasma membrane pore formation induces chemokine production in survivors of regulated necrosis

Sensing plasma membrane pore formation induces chemokine production in survivors of regulated necrosis

  • Dev Cell. 2022 Jan 24;57(2):228-245.e6. doi: 10.1016/j.devcel.2021.12.015.
Weihong Wang 1,  Joshua S Prokopec 1,  Yixin Zhang 1,  Maria Sukhoplyasova 1,  Himaly Shinglot 1,  Man-Tzu Wang 2,  Andreas Linkermann 3,  Jacob Stewart-Ornstein 4,  Yi-Nan Gong 5
Affiliations

Affiliations

  • 1 Hillman Cancer Center, UPMC, Pittsburgh, PA 15232, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 2 Hillman Cancer Center, UPMC, Pittsburgh, PA 15232, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 3 Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden 01307, Germany.
  • 4 Hillman Cancer Center, UPMC, Pittsburgh, PA 15232, USA; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: jas632@pitt.edu.
  • 5 Hillman Cancer Center, UPMC, Pittsburgh, PA 15232, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: yngong@pitt.edu.
PMID: 35016014 DOI: 10.1016/j.devcel.2021.12.015
Abstract

Although overwhelming plasma membrane integrity loss leads to Cell Lysis and necrosis, cells can tolerate a limited level of plasma membrane damage, undergo ESCRT-III-mediated repair, and survive. Here, we find that cells which undergo limited plasma membrane damage from the pore-forming actions of MLKL, GSDMD, perforin, or detergents experience local activation of PKCs through CA2+ influx at the damage sites. S660-phosphorylated PKCs subsequently activate the TAK1/IKKs axis and RelA/Cux1 complex to trigger chemokine expressions. We observe that in late-stage cancers, cells with active MLKL show expression of CXCL8. Similar expression induction is also found in ischemia-injured kidneys. Chemokines generated in this manner are also indispensable for recruiting immune cells to the dead and dying cells. This plasma membrane integrity-sensing pathway is similar to the well-established yeast cell wall integrity signaling pathway at molecular level, and this suggests an evolutionary conserved mechanism to respond to the cellular barrier damage.

Keywords

GSDMD; MLKL; PKC; chemokines; necroptosis; plasma membrane damage; pore forming; pyroptosis; regulated necrosis; sub-lethal.

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