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<p>Plasma membrane rupture (PMR), once considered a passive event in necrosis, is actively executed by ninjurin-1 (NINJ1). Although PMR is a well-documented phenomenon across animal species, its molecular mechanism and immunological function in early diverging jawed vertebrates remain unclear. Herein, we identify a functional homolog of NINJ1 in turbot. Ectopic expression of turbot NINJ1 effectively lyses the plasma membrane, leading to rapid PMR and massive release of cellular contents. Given that turbot NINJ1 has two transmembrane helices, it could distribute within membrane-bound organelles and the plasma membrane as PMR progresses. Co-expression with turbot gasdermin significantly amplifies NINJ1-mediated PMR, even when both proteins are present at non-cytotoxic levels. Structural analysis reveals the importance of its extracellular and transmembrane helices, with specific functional residues crucial for its PMR-inducing activity. Bacterial infection upregulates NINJ1 and activates pyroptosis signaling pathway, and provokes strong proinflammatory responses. Inhibiting NINJ1 improves fish survival, whereas blocking pyroptosis actually dampens host antimicrobial immunity. Collectively, the present findings delineate a mechanistically distinct role of NINJ1 in regulating programmed cell death in turbot, highlighting the complex and bifunctional nature of cell death in teleost immunity.</p>

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Ninjurin-1 executes plasma membrane rupture and impairs anti-microbial immunity in an early jawed vertebrate

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月23日

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  • Xiaotong Jin,
  • Liming Yuan,
  • Chunyan Sun,
  • Shuai Jiang

摘要

Plasma membrane rupture (PMR), once considered a passive event in necrosis, is actively executed by ninjurin-1 (NINJ1). Although PMR is a well-documented phenomenon across animal species, its molecular mechanism and immunological function in early diverging jawed vertebrates remain unclear. Herein, we identify a functional homolog of NINJ1 in turbot. Ectopic expression of turbot NINJ1 effectively lyses the plasma membrane, leading to rapid PMR and massive release of cellular contents. Given that turbot NINJ1 has two transmembrane helices, it could distribute within membrane-bound organelles and the plasma membrane as PMR progresses. Co-expression with turbot gasdermin significantly amplifies NINJ1-mediated PMR, even when both proteins are present at non-cytotoxic levels. Structural analysis reveals the importance of its extracellular and transmembrane helices, with specific functional residues crucial for its PMR-inducing activity. Bacterial infection upregulates NINJ1 and activates pyroptosis signaling pathway, and provokes strong proinflammatory responses. Inhibiting NINJ1 improves fish survival, whereas blocking pyroptosis actually dampens host antimicrobial immunity. Collectively, the present findings delineate a mechanistically distinct role of NINJ1 in regulating programmed cell death in turbot, highlighting the complex and bifunctional nature of cell death in teleost immunity.