FERMT2 links cortical actin structures, plasma membrane tension and focal adhesion function to stabilize podocyte morphology.
FERMT2 links cortical actin structures, plasma membrane tension and focal adhesion function to stabilize podocyte morphology.
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DOI：
10.1016/j.matbio.2018.01.003
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发表时间：
2018-08
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通讯作者：
M. Yasuda‐Yamahara;M. Yasuda‐Yamahara;M. Rogg;J. Frimmel;P. Trachte;Martin Helmstaedter;P. Schroder;P. Schroder;M. Schiffer;M. Schiffer;C. Schell;C. Schell;T. Huber;T. Huber
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作者：
M. Yasuda‐Yamahara;M. Yasuda‐Yamahara;M. Rogg;J. Frimmel;P. Trachte;Martin Helmstaedter;P. Schroder;P. Schroder;M. Schiffer;M. Schiffer;C. Schell;C. Schell;T. Huber;T. Huber
足细胞突起的简化和回缩，通常称为足突消失，是在大多数肾小球疾病中观察到的统一病理模式，包括局灶节段性肾小球硬化症。然而，它仍然是不完全了解如何相互作用的皮质肌动蛋白结构，肌动球蛋白收缩性和局灶性粘连，正在精心策划，以控制足突形态在健康和疾病。通过揭示Fermitin家族成员2（FERMT 2或kindlin-2）在足细胞中的功能作用，我们现在提供证据，细胞-细胞外基质（ECM）相互作用如何调节膜张力和肌动球蛋白收缩性。通过在一组体内系统中以及在CRISPR/Cas9修饰的人类足细胞中缺失FERMT 2来应用遗传建模方法。FERMT 2的缺失导致皮质肌动蛋白组成改变，细胞皮质不稳定，与质膜起泡和局部粘连重塑相关。我们进一步表明，FERMT 2敲除足细胞具有高水平的RhoA激活和伴随的肌动球蛋白收缩性增加。肌动球蛋白张力的抑制逆转膜起泡表型。因此，我们的研究结果建立了细胞-基质粘附，皮质肌动蛋白结构和质膜张力之间的直接联系，允许更好地解释足突消失的细胞形态学变化。
Simplification and retraction of podocyte protrusions, generally termed as foot process effacement, is a uniform pathological pattern observed in the majority of glomerular disease, including focal segmental glomerulosclerosis. However, it is still incompletely understood how the interaction of cortical actin structures, actomyosin contractility and focal adhesions, is being orchestrated to control foot process morphology in health and disease. By uncovering the functional role of fermitin family member 2 (FERMT2 or kindlin-2) in podocytes, we provide now evidence, how cell-extracellular matrix (ECM) interactions modulate membrane tension and actomyosin contractility. A genetic modeling approach was applied by deleting FERMT2 ina set ofin vivo systems as well as in CRISPR/Cas9 modified human podocytes. Loss of FERMT2 results in altered cortical actin composition, cell cortex destabilization associated with plasma membrane blebbing and a remodeling of focal adhesions. We further show that FERMT2 knockout podocytes have high levels of RhoA activation and concomitantly increased actomyosin contractility. Inhibition of actomyosin tension reverses the membrane blebbing phenotype. Thus, our findings establish a direct link between cell-matrix adhesions, cortical actin structures and plasma membrane tension allowing to better explain cell morphological changes in foot process effacement.