2. Academic Validation
  3. NINJ1 mediates plasma membrane rupture by cutting and releasing membrane disks

NINJ1 mediates plasma membrane rupture by cutting and releasing membrane disks

  • Cell. 2024 Apr 25;187(9):2224-2235.e16. doi: 10.1016/j.cell.2024.03.008.
Liron David 1,  Jazlyn P Borges 2,  L Robert Hollingsworth 1,  Allen Volchuk 3,  Isabelle Jansen 4,  Evelyn Garlick 4,  Benjamin E Steinberg 5,  Hao Wu 6
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
  • 2 Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON, Canada.
  • 3 Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
  • 4 Abberior Instruments GmbH, Göttingen, Germany.
  • 5 Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Department of Anesthesia and Pain Medicine, Hospital for Sick Children, Toronto, ON, Canada; Department of Anesthesiology and Pain Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. Electronic address: wu@crystal.harvard.edu.
PMID: 38614101 DOI: 10.1016/j.cell.2024.03.008
Abstract

The membrane protein NINJ1 mediates plasma membrane rupture in Pyroptosis and Other lytic cell death pathways. Here, we report the cryo-EM structure of a NINJ1 oligomer segmented from NINJ1 rings. Each NINJ1 subunit comprises amphipathic (⍺1, ⍺2) and transmembrane (TM) helices (⍺3, ⍺4) and forms a chain of subunits, mainly by the TM helices and ⍺1. ⍺3 and ⍺4 are kinked, and the Gly residues are important for function. The NINJ1 oligomer possesses a concave hydrophobic side that should face the membrane and a convex hydrophilic side formed by ⍺1 and ⍺2, presumably upon activation. This structural observation suggests that NINJ1 can form membrane disks, consistent with membrane fragmentation by recombinant NINJ1. Live-cell and super-resolution imaging uncover ring-like structures on the plasma membrane that are released into the culture supernatant. Released NINJ1 encircles a membrane inside, as shown by lipid staining. Therefore, NINJ1-mediated membrane disk formation is different from gasdermin-mediated pore formation, resulting in membrane loss and plasma membrane rupture.

Keywords

NINJ1; NINJ2; Ninjurin1; Ninjurin2; cryo-EM; inflammasome; inflammation; lytic cell death; plasma membrane rupture; pyroptosis.

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