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.
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
Sanja
S
Sever
Mehmet M
MM
Altintas
Sharif R
SR
Nankoe
Clemens C
CC
Möller
David
D
Ko
Changli
C
Wei
Joel
J
Henderson
Elizabetta C
EC
del Re
Lianne
L
Hsing
Ann
A
Erickson
Clemens D
CD
Cohen
Matthias
M
Kretzler
Dontscho
D
Kerjaschki
Alexander
A
Rudensky
Boris
B
Nikolic
Jochen
J
Reiser
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