Journal Article

Plekhh2, a novel podocyte protein downregulated in human focal segmental glomerulosclerosis, is involved in matrix adhesion and actin dynamics

Sun, Ying, Brismar, Hjalmar, Uhlen, Mathias, Önfelt, Björn, Perisic, Ljubica, Tryggvason, Karl, Dunér, Fredrik, Betsholtz, Christer, Wernerson, Annika, Patrakka, Jaakko, Pikkarainen, Timo, Lal, Mark, Hulkko, Jenny, Hultenby, Kjell

2012

Overview

Pleckstrin homology domain–containing, family H (with MyTH4 domain), member 2 (Plekhh2) is a 1491-residue intracellular protein highly enriched in renal glomerular podocytes for which no function has been ascribed. Analysis of renal biopsies from patients with focal segmental glomerulosclerosis revealed a significant reduction in total podocyte Plekhh2 expression compared to controls. Sequence analysis indicated a putative α-helical coiled-coil segment as the only recognizable domain within the N-terminal half of the polypeptide, while the C-terminal half contains two PH, a MyTH4, and a FERM domain. We identified a phosphatidylinositol-3-phosphate consensus-binding site in the PH1 domain required for Plekhh2 localization to peripheral regions of cell lamellipodia. The N-terminal half of Plekkh2 is not necessary for lamellipodial targeting but mediates self-association. Yeast two-hybrid screening showed that Plekhh2 directly interacts through its FERM domain with the focal adhesion protein Hic-5 and actin. Plekhh2 and Hic-5 coprecipitated and colocalized at the soles of podocyte foot processes in situ and Hic-5 partially relocated from focal adhesions to lamellipodia in Plekhh2-expressing podocytes. In addition, Plekhh2 stabilizes the cortical actin cytoskeleton by attenuating actin depolymerization. Our findings suggest a structural and functional role for Plekhh2 in the podocyte foot processes.

• Publisher: Elsevier Inc,Nature Publishing Group,Elsevier Limited
• Subject: Actin Cytoskeleton - metabolism / Actin Cytoskeleton - pathology / Actins - metabolism / Animals / Binding Sites / Biological and medical sciences / Biopsy / Case-Control Studies / cell biology and structure / cell-matrix interactions / Cell-Matrix Junctions - metabolism / Cercopithecus aethiops / CHO Cells / COS Cells / Cricetinae / Cricetulus / Cytoskeletal Proteins - metabolism / cytoskeleton / Disease Models, Animal / DNA-Binding Proteins - metabolism / Down-Regulation / Glomerulonephritis / Glomerulosclerosis, Focal Segmental - genetics / Glomerulosclerosis, Focal Segmental - metabolism / Glomerulosclerosis, Focal Segmental - pathology / HEK293 Cells / Humans / Intracellular Signaling Peptides and Proteins - chemistry / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / LIM Domain Proteins - metabolism / Medical sciences / Mice / Nephrology. Urinary tract diseases / Nephropathies. Renovascular diseases. Renal failure / Phosphatidylinositol Phosphates - metabolism / podocyte / Podocytes - metabolism / Podocytes - pathology / protein interaction / Protein Interaction Domains and Motifs / Protein Interaction Mapping / Protein Structure, Secondary / Protein Transport / Pseudopodia - metabolism / Sequence Analysis, Protein / Transfection / Two-Hybrid System Techniques