Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease.
Kidney podocytes and their foot processes maintain the ultrafiltration barrier and prevent urinary protein loss (proteinuria). Here we show that the GTPase dynamin is essential for podocyte function. During proteinuric kidney disease, induction of cytoplasmic cathepsin L leads to cleavage of dynamin at an evolutionary conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria. Dynamin mutants that lack the cathepsin L site, or render the cathepsin L site inaccessible through dynamin self-assembly, are resistant to cathepsin L cleavage. When delivered into mice, these mutants restored podocyte function and resolve proteinuria. Our study identifies dynamin as a critical regulator of renal permselectivity that is specifically targeted by proteolysis under pathological conditions.
Sever
Sanja
S
Department of Medicine, Nephrology Division and Program in Glomerular Disease, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts 02129, USA. ssever@partners.org
Altintas
Mehmet M
MM
Nankoe
Sharif R
SR
Möller
Clemens C
CC
Ko
David
D
Wei
Changli
C
Henderson
Joel
J
del Re
Elizabetta C
EC
Hsing
Lianne
L
Erickson
Ann
A
Cohen
Clemens D
CD
Kretzler
Matthias
M
Kerjaschki
Dontscho
D
Rudensky
Alexander
A
Nikolic
Boris
B
Reiser
Jochen
J
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D050199:Podocytes / Q000201:enzymology* / Q000473:pathology; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D000199:Actins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D034281:Dynamins