NINJ1 mediates plasma membrane rupture during lytic cell death

Nobuhiko Kayagaki (), Opher S. Kornfeld, Bettina L. Lee, Irma B. Stowe, Karen O’Rourke, Qingling Li, Wendy Sandoval, Donghong Yan, Jing Kang, Min Xu, Juan Zhang, Wyne P. Lee, Brent S. McKenzie, Gözde Ulas, Jian Payandeh, Merone Roose-Girma, Zora Modrusan, Rohit Reja, Meredith Sagolla, Joshua D. Webster, Vicky Cho, T. Daniel Andrews, Lucy X. Morris, Lisa A. Miosge, Christopher C. Goodnow, Edward M. Bertram and Vishva M. Dixit ()
Additional contact information
Nobuhiko Kayagaki: Genentech Inc.
Opher S. Kornfeld: Genentech Inc.
Bettina L. Lee: Genentech Inc.
Irma B. Stowe: Genentech Inc.
Karen O’Rourke: Genentech Inc.
Qingling Li: Proteomics and Lipidomics, Genentech Inc.
Wendy Sandoval: Proteomics and Lipidomics, Genentech Inc.
Donghong Yan: Genentech Inc.
Jing Kang: Genentech Inc.
Min Xu: Genentech Inc.
Juan Zhang: Genentech Inc.
Wyne P. Lee: Genentech Inc.
Brent S. McKenzie: Genentech Inc.
Gözde Ulas: Genentech Inc.
Jian Payandeh: Genentech Inc.
Merone Roose-Girma: Genentech Inc.
Zora Modrusan: Proteomics and Lipidomics, Genentech Inc.
Rohit Reja: Genentech Inc.
Meredith Sagolla: Genentech Inc.
Joshua D. Webster: Genentech Inc.
Vicky Cho: The Australian National University
T. Daniel Andrews: The Australian National University
Lucy X. Morris: The Australian National University
Lisa A. Miosge: The Australian National University
Christopher C. Goodnow: Garvan Institute of Medical Research
Edward M. Bertram: The Australian National University
Vishva M. Dixit: Genentech Inc.

Nature, 2021, vol. 591, issue 7848, 131-136

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03218-7

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