Molecular basis of the functional podocin-nephrin complex
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Molecular basis of the functional podocin-nephrin complex : mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. / Huber, Tobias B; Simons, Matias; Hartleben, Björn; Sernetz, Leonie; Schmidts, Miriam; Gundlach, Enken; Saleem, Moin A; Walz, Gerd; Benzing, Thomas.
In: HUM MOL GENET, Vol. 12, No. 24, 15.12.2003, p. 3397-405.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Molecular basis of the functional podocin-nephrin complex
T2 - mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains
AU - Huber, Tobias B
AU - Simons, Matias
AU - Hartleben, Björn
AU - Sernetz, Leonie
AU - Schmidts, Miriam
AU - Gundlach, Enken
AU - Saleem, Moin A
AU - Walz, Gerd
AU - Benzing, Thomas
PY - 2003/12/15
Y1 - 2003/12/15
N2 - Hereditary nephrotic syndrome is a heterogeneous disease, characterized by heavy proteinuria and renal failure. Mutations of NPHS1 or NPHS2, the genes encoding for nephrin and podocin, lead to early onset of heavy proteinuria, and rapid progression to end-stage renal disease, suggesting that both proteins are essential for the integrity of the glomerular filter. Podocin is a stomatin protein family member with a predicted hairpin-like structure localizing to the insertion site of the slit diaphragm of podocytes, the visceral glomerular epithelial cells of the kidney. Here we investigate the pathomechanisms of different disease-causing podocin mutations. We show that wild-type podocin is targeted to the plasma membrane, and forms homo-oligomers involving the carboxy and amino terminal cytoplasmic domains. The association of podocin with specialized lipid raft microdomains of the plasma membrane was a prerequisite for recruitment of nephrin into rafts. In contrast, disease-causing mutations of podocin (R138Q and R138X) failed to recruit nephrin into rafts either because these mutants were retained in the endoplasmic reticulum (R138Q), or because they failed to associate with rafts (R138X) despite their presence in the plasma membrane. None of the mutants did augment nephrin signaling, suggesting that lipid raft targeting facilitates nephrin signaling. Our findings demonstrate that the failure of mutant podocin to recruit nephrin into lipid rafts may be essential for the pathogenesis of NPHS2.
AB - Hereditary nephrotic syndrome is a heterogeneous disease, characterized by heavy proteinuria and renal failure. Mutations of NPHS1 or NPHS2, the genes encoding for nephrin and podocin, lead to early onset of heavy proteinuria, and rapid progression to end-stage renal disease, suggesting that both proteins are essential for the integrity of the glomerular filter. Podocin is a stomatin protein family member with a predicted hairpin-like structure localizing to the insertion site of the slit diaphragm of podocytes, the visceral glomerular epithelial cells of the kidney. Here we investigate the pathomechanisms of different disease-causing podocin mutations. We show that wild-type podocin is targeted to the plasma membrane, and forms homo-oligomers involving the carboxy and amino terminal cytoplasmic domains. The association of podocin with specialized lipid raft microdomains of the plasma membrane was a prerequisite for recruitment of nephrin into rafts. In contrast, disease-causing mutations of podocin (R138Q and R138X) failed to recruit nephrin into rafts either because these mutants were retained in the endoplasmic reticulum (R138Q), or because they failed to associate with rafts (R138X) despite their presence in the plasma membrane. None of the mutants did augment nephrin signaling, suggesting that lipid raft targeting facilitates nephrin signaling. Our findings demonstrate that the failure of mutant podocin to recruit nephrin into lipid rafts may be essential for the pathogenesis of NPHS2.
KW - Cell Membrane
KW - HeLa Cells
KW - Humans
KW - Intracellular Signaling Peptides and Proteins
KW - Membrane Proteins
KW - Mutation
KW - Nephrotic Syndrome
KW - Plasmids
KW - Proteins
KW - Signal Transduction
KW - Transfection
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1093/hmg/ddg360
DO - 10.1093/hmg/ddg360
M3 - SCORING: Journal article
C2 - 14570703
VL - 12
SP - 3397
EP - 3405
JO - HUM MOL GENET
JF - HUM MOL GENET
SN - 0964-6906
IS - 24
ER -