2. Academic Validation
  3. NINJ1 mediates plasma membrane rupture during lytic cell death

NINJ1 mediates plasma membrane rupture during lytic cell death

  • Nature. 2021 Mar;591(7848):131-136. doi: 10.1038/s41586-021-03218-7.
Nobuhiko Kayagaki 1,  Opher S Kornfeld 2,  Bettina L Lee 2,  Irma B Stowe 2,  Karen O'Rourke 2,  Qingling Li 3,  Wendy Sandoval 3,  Donghong Yan 4,  Jing Kang 4,  Min Xu 4,  Juan Zhang 4,  Wyne P Lee 4,  Brent S McKenzie 4,  Gözde Ulas 5,  Jian Payandeh 6,  Merone Roose-Girma 7,  Zora Modrusan 3,  Rohit Reja 8,  Meredith Sagolla 9,  Joshua D Webster 9,  Vicky Cho 10 11,  T Daniel Andrews 11,  Lucy X Morris 10,  Lisa A Miosge 10 11,  Christopher C Goodnow 12 13,  Edward M Bertram 10 11,  Vishva M Dixit 14
Affiliations

Affiliations

  • 1 Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA, USA. kayagaki@gene.com.
  • 2 Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA, USA.
  • 3 Department of Microchemistry, Proteomics and Lipidomics, Genentech Inc., South San Francisco, CA, USA.
  • 4 Department of Translational Immunology, Genentech Inc., South San Francisco, CA, USA.
  • 5 Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, USA.
  • 6 Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA.
  • 7 Department of Molecular Biology, Genentech Inc., South San Francisco, CA, USA.
  • 8 Department of Bioinformatics, Genentech Inc., South San Francisco, CA, USA.
  • 9 Department of Pathology, Genentech Inc., South San Francisco, CA, USA.
  • 10 The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
  • 11 Department of Immunology and Infectious Diseases, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
  • 12 Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • 13 Cellular Genomics Futures Institute, UNSW Sydney, Sydney, New South Wales, Australia.
  • 14 Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA, USA. dixit@gene.com.
PMID: 33472215 DOI: 10.1038/s41586-021-03218-7
Abstract

Plasma membrane rupture (PMR) is the final cataclysmic event in lytic cell death. PMR releases intracellular molecules known as damage-associated molecular patterns (DAMPs) that propagate the inflammatory response1-3. The underlying mechanism of PMR, however, is unknown. Here we show that the cell-surface NINJ1 protein4-8, which contains two transmembrane regions, has an essential role in the induction of PMR. A forward-genetic screen of randomly mutagenized mice linked NINJ1 to PMR. Ninj1-/- macrophages exhibited impaired PMR in response to diverse inducers of pyroptotic, necrotic and apoptotic cell death, and were unable to release numerous intracellular proteins including HMGB1 (a known DAMP) and LDH (a standard measure of PMR). Ninj1-/- macrophages died, but with a distinctive and persistent ballooned morphology, attributable to defective disintegration of bubble-like herniations. Ninj1-/- mice were more susceptible than wild-type mice to Infection with Citrobacter rodentium, which suggests a role for PMR in anti-bacterial host defence. Mechanistically, NINJ1 used an evolutionarily conserved extracellular domain for oligomerization and subsequent PMR. The discovery of NINJ1 as a mediator of PMR overturns the long-held idea that cell death-related PMR is a passive event.

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