Institute of Surgical Pathology, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany.
Department of Medicine IV, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany.
Cell Rep. 2021 Mar 23;34(12):108883. doi: 10.1016/j.celrep.2021.108883.
The integrity of the kidney filtration barrier essentially relies on the balanced interplay of podocytes and the glomerular basement membrane (GBM). Here, we show by analysis of in vitro and in vivo models that a loss of the podocyte-specific FERM-domain protein EPB41L5 results in impaired extracellular matrix (ECM) assembly. By using quantitative proteomics analysis of the secretome and matrisome, we demonstrate a shift in ECM composition characterized by diminished deposition of core GBM components, such as LAMA5. Integrin adhesome proteomics reveals that EPB41L5 recruits PDLIM5 and ACTN4 to integrin adhesion complexes (IACs). Consecutively, EPB41L5 knockout podocytes show insufficient maturation of integrin adhesion sites, which translates into impaired force transmission and ECM assembly. These observations build the framework for a model in which EPB41L5 functions as a cell-type-specific regulator of the podocyte adhesome and controls a localized adaptive module in order to prevent podocyte detachment and thereby ensures GBM integrity.
肾脏滤过屏障的完整性主要依赖于足细胞和肾小球基底膜（GBM）的平衡相互作用。在这里，我们通过分析体外和体内模型表明，足细胞特异性 FERM 结构域蛋白 EPB41L5 的缺失会导致细胞外基质（ECM）组装受损。通过对分泌组和基质组的定量蛋白质组学分析，我们证明 ECM 组成发生了变化，特征是核心 GBM 成分如 LAMA5 的沉积减少。整联蛋白黏附体蛋白质组学揭示 EPB41L5 招募 PDLIM5 和 ACTN4 到整联蛋白黏附复合物（IAC）。随后，EPB41L5 敲除足细胞表现出整合素黏附位点的成熟不足，这转化为细胞内力传递和 ECM 组装受损。这些观察结果为 EPB41L5 作为足细胞黏附体的细胞特异性调节剂的模型提供了框架，并控制局部适应性模块，以防止足细胞脱离，从而确保 GBM 的完整性。
