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1.
EMBO Rep ; 25(9): 3870-3895, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38969946

RESUMEN

Plasma membrane repair is a fundamental homeostatic process of eukaryotic cells. Here, we report a new function for the conserved cytoskeletal proteins known as septins in the repair of cells perforated by pore-forming toxins or mechanical disruption. Using a silencing RNA screen, we identified known repair factors (e.g. annexin A2, ANXA2) and novel factors such as septin 7 (SEPT7) that is essential for septin assembly. Upon plasma membrane injury, the septin cytoskeleton is extensively redistributed to form submembranous domains arranged as knob and loop structures containing F-actin, myosin IIA, S100A11, and ANXA2. Formation of these domains is Ca2+-dependent and correlates with plasma membrane repair efficiency. Super-resolution microscopy revealed that septins and F-actin form intertwined filaments associated with ANXA2. Depletion of SEPT7 prevented ANXA2 recruitment and formation of submembranous actomyosin domains. However, ANXA2 depletion had no effect on domain formation. Collectively, our data support a novel septin-based mechanism for resealing damaged cells, in which the septin cytoskeleton plays a key structural role in remodeling the plasma membrane by promoting the formation of SEPT/F-actin/myosin IIA/ANXA2/S100A11 repair domains.


Asunto(s)
Actinas , Anexina A2 , Membrana Celular , Citoesqueleto , Septinas , Septinas/metabolismo , Septinas/genética , Humanos , Anexina A2/metabolismo , Anexina A2/genética , Membrana Celular/metabolismo , Citoesqueleto/metabolismo , Actinas/metabolismo , Miosina Tipo IIA no Muscular/metabolismo , Miosina Tipo IIA no Muscular/genética , Células HeLa , Calcio/metabolismo , Proteínas S100/metabolismo , Proteínas S100/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética
2.
bioRxiv ; 2024 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-37503091

RESUMEN

Mammalian cells are frequently exposed to mechanical and biochemical stressors resulting in plasma membrane injuries. Repair mechanisms reseal the plasma membrane to restore homeostasis and prevent cell death. In the present work, a silencing RNA screen was performed to uncover plasma membrane repair mechanisms of cells exposed to a pore-forming toxin (listeriolysin O). This screen identified molecules previously known to repair the injured plasma membrane such as annexin A2 (ANXA2) as well as novel plasma membrane repair candidate proteins. Of the novel candidates, we focused on septin 7 (SEPT7) because the septins are an important family of conserved eukaryotic cytoskeletal proteins. Using diverse experimental approaches, we established for the first time that SEPT7 plays a general role in plasma membrane repair of cells perforated by pore-forming toxins and mechanical wounding. Remarkably, upon cell injury, the septin cytoskeleton is extensively redistributed in a Ca 2+ -dependent fashion, a hallmark of plasma membrane repair machineries. The septins reorganize into subplasmalemmal domains arranged as knob and loop (or ring) structures containing F-actin, myosin II, and annexin A2 (ANXA2) and protrude from the cell surface. Importantly, the formation of these domains correlates with the plasma membrane repair efficiency. Super-resolution microscopy shows that septins and actin are arranged in intertwined filaments associated with ANXA2. Silencing SEPT7 expression prevented the formation of the F-actin/myosin II/ANXA2 domains, however, silencing expression of ANXA2 had no observable effect on their formation. These results highlight the key structural role of the septins in remodeling the plasma membrane and in the recruitment of the repair molecule ANXA2. Collectively, our data support a novel model in which the septin cytoskeleton acts as a scaffold to promote the formation of plasma membrane repair domains containing contractile F-actin and annexin A2.

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