Institute of Pharmacology, University of Marburg, Marburg, Germany.
Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
PLoS One. 2021 May 27;16(5):e0252428. doi: 10.1371/journal.pone.0252428. eCollection 2021.
Diaphanous related formins are highly conserved proteins regulated by Rho-GTPases that act as actin nucleation and assembly factors. Here we report the functional characterization of a non-inherited heterozygous FMNL2 p.L136P mutation carried by a patient who presented with severe very early onset inflammatory bowel disease (IBD). We found that the FMNL2 L136P protein displayed subcellular mislocalization and deregulated protein autoinhibition indicating gain-of-function mechanism. Expression of FMNL2 L136P impaired cell spreading as well as filopodia formation. THP-1 macrophages expressing FMNL2 L136P revealed dysregulated podosome formation and a defect in matrix degradation. Our data indicate that the L136P mutation affects cellular actin dynamics in fibroblasts and immune cells such as macrophages.
细丝相关形态发生蛋白是受 Rho-GTPases 调控的高度保守蛋白，它们作为肌动蛋白成核和组装因子发挥作用。在这里，我们报告了由一位患有严重早发性炎症性肠病（IBD）的患者携带的非遗传性杂合 FMNL2 p.L136P 突变的功能特征。我们发现，FMNL2 L136P 蛋白显示亚细胞定位错误和蛋白自身抑制失调，表明存在获得性功能机制。FMNL2 L136P 的表达会损害细胞铺展以及丝状伪足的形成。表达 FMNL2 L136P 的 THP-1 巨噬细胞显示出 Podosome 形成的失调和基质降解的缺陷。我们的数据表明，L136P 突变会影响成纤维细胞和免疫细胞（如巨噬细胞）中的细胞肌动蛋白动力学。
