Membrane Tension Drives Opening of NINJ1 Lesions in Dying Cells

Membrane Tension Drives Opening of NINJ1 Lesions in Dying Cells | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Membrane Tension Drives Opening of NINJ1 Lesions in Dying Cells Petr Broz, Ella Hartenian, Elliott Bernard, Giulia Amirati, Hubert Leloup, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9075362/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Ninjurin-1 (NINJ1) executes cell lysis by polymerizing into filaments, yet how these form membrane lesions is unknown. Integrating cell-based assays with molecular dynamics simulations, we demonstrate that NINJ1-driven membrane rupture starts with the lateral association of NINJ1 dimers into double filaments. Subsequently, swelling of necrotic cells increases plasma membrane tension, leading to separation of the filament interface and NINJ1 lesion opening. Inhibiting cell swelling prevents this increase in tension, blocking NINJ1-mediated plasma membrane rupture without disrupting NINJ1 oligomerization, implicating membrane tension as key for opening NINJ1 lesions. The NINJ1 homolog NINJ2 oligomerizes but fails to form membrane lesions during cell death due to the greater stability of its dimer. Finally, using atomic force microscopy of NINJ1-containing proteoliposomes, we show that NINJ1 forms large pores by stabilizing membrane edges. In summary, our findings support a model whereby membrane tension drives a zipper-like opening of NINJ1 double filaments, initiating necrotic cell lysis. Biological sciences/Immunology/Cell death and immune response Biological sciences/Immunology/Inflammation Biological sciences/Immunology/Innate immune cells/Monocytes and macrophages Biological sciences/Biological techniques/Biophysical methods/Atomic force microscopy Biological sciences/Biophysics/Membrane biophysics Cell death NINJ1 ferroptosis PMR inflammation necrosis Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Movie4.mpg Movie 4 Movie2.avi Movie 2 Movie1.avi Movie 1 Movie3.mpg Movie 3 Movie6.mp4 Movie 6 Movie5.mpg Movie 5 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

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