EPB41L5 controls podocyte extracellular matrix assembly by adhesome-dependent force transmission
Jasmin I. Maier,
Manuel Rogg,
Martin Helmstädter,
Alena Sammarco,
Oliver Schilling,
Benedikt Sabass,
Jeffrey H. Miner,
Jörn Dengjel,
Gerd Walz,
Martin Werner,
Tobias B. Huber,
Christoph Schell
Affiliations
Jasmin I. Maier
Institute of Surgical Pathology, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany
Manuel Rogg
Institute of Surgical Pathology, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany
Martin Helmstädter
Department of Medicine IV, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany
Alena Sammarco
Institute of Surgical Pathology, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany
Oliver Schilling
Institute of Surgical Pathology, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany
Benedikt Sabass
Bacteriology and Mycology, Institute for Infectious Diseases and Zoonoses, Department of Veterinary Sciences, LMU Munich, 80539 Munich, Germany
Jeffrey H. Miner
Division of Nephrology, Washington University School of Medicine, St. Louis, MO 63110, USA
Jörn Dengjel
Department of Biology, University of Fribourg, Fribourg 1700, Switzerland
Gerd Walz
Department of Medicine IV, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany
Martin Werner
Institute of Surgical Pathology, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany
Tobias B. Huber
III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
Christoph Schell
Institute of Surgical Pathology, Faculty of Medicine, University Medical Center Freiburg, Freiburg 79106, Germany; Berta-Ottenstein Program, Medical Faculty, University Medical Center, Freiburg 79106, Germany; Corresponding author
Summary: 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.
