Pore size dynamics control complex volume swelling in pyroptosis

• 成果类型: Article
• 署名作者: Bastien, Estelle; Duprez, Guillaume; Delanoe-Ayari, Helene; Leloup, Hubert; Riviere, Charlotte; Petrilli, Virginie; Recho, Pierre; Monnier, Sylvain
• 署名单位: Universite Lyon 1; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Physics (INP); Centre National de la Recherche Scientifique (CNRS); Communaute Universite Grenoble Alpes; CNRS - Institute of Physics (INP); Universite Grenoble Alpes (UGA); Universite Lyon 1; Centre National de la Recherche Scientifique (CNRS); UNICANCER; Institut National de la Sante et de la Recherche Medicale (Inserm); CNRS - National Institute for Biology (INSB); Centre Leon Berard
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2508022123
• 发表日期: 2026-01-27
• 页码: e2508022123
• 关键词: cell death; pyroptosis; VOLUME REGULATION; membrane permeability; GASDERMIN-D PORE; cell; gsdmd; INTERLEUKIN-1-BETA; secretion; membranes

摘要

Pyroptosis, an inflammatory form of cell death, is characterized by massive cell swelling and plasma membrane rupture. Although swelling was recently shown to occur in two steps, the molecular and biophysical mechanisms driving this process remained unclear. Using fast quantitative microscopy, we reveal that between the two swelling phases, cell volume transiently stabilizes despite sustained plasma membrane permeability to ions and small molecules. From a biophysical perspective, the existence of such a plateau is puzzling, as ion pumps should not be able to regulate cell volume under these conditions. To address this, we developed a physical model based on an ion pump and leak framework that incorporates the dynamics of nonselective pore formation. Experimentally, we demonstrate that the plateau phase is controlled by the dynamics of the gasdermin D (GSDMD) pore enlargement, which is modulated by ninjurin-1 (Ninj1) activation, possibly through intracellular calcium. Ninj1-mediated lesions are also required for the second swelling phase. We further show that fully opened GSDMD pores display an effective hydrodynamic radius slightly above 1.9 nm, providing an in situ upper bound for pore size. Together, our findings demonstrate that pyroptotic volume dysregulation emerges from the successive and interdependent actions of GSDMD and Ninj1, each imparting distinct permeability regimes associated with increased water filtration and decreased ion selectivity due to pore opening. These insights bridge molecular and biophysical perspectives on lytic cell death and may inform the broader understanding of membrane rupture in inflammatory and pathological contexts.