title: Novel functional complexity of polycystin-1 by GPS cleavage in vivo: role in polycystic kidney disease.
abstract: Polycystin-1 (Pc1) cleavage at the G protein-coupled receptor (GPCR) proteolytic site (GPS) is required for normal kidney morphology in humans and mice. We found a complex pattern of endogenous Pc1 forms by GPS cleavage. GPS cleavage generates not only the heterodimeric cleaved full-length Pc1 (Pc1(cFL)) in which the N-terminal fragment (NTF) remains noncovalently associated with the C-terminal fragment (CTF) but also a novel (Pc1) form (Pc1(deN)) in which NTF becomes detached from CTF. Uncleaved Pc1 (Pc1(U)) resides primarily in the endoplasmic reticulum (ER), whereas both Pc1(cFL) and Pc1(deN) traffic through the secretory pathway in vivo. GPS cleavage is not a prerequisite, however, for Pc1 trafficking in vivo. Importantly, Pc1(deN) is predominantly found at the plasma membrane of renal epithelial cells. By functional genetic complementation with five Pkd1 mouse models, we discovered that CTF plays a crucial role in Pc1(deN) trafficking. Our studies support GPS cleavage as a critical regulatory mechanism of Pc1 biogenesis and trafficking for proper kidney development and homeostasis.
authors: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Université de Montreal, Faculté de Médecine, Montreal, Quebec, Canada.
authors: Almira
authors: A
authors: Kurbegovic
authors: Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Hyunho
authors: H
authors: Kim
authors: Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Hangxue
authors: H
authors: Xu
authors: Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Shengqiang
authors: S
authors: Yu
authors: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Université de Montreal, Faculté de Médecine, Montreal, Quebec, Canada.
authors: Julie
authors: J
authors: Cruanès
authors: Department of Clinical Laboratory Sciences and the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors: Robin L
authors: RL
authors: Maser
authors: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors: Alessandra
authors: A
authors: Boletta
authors: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Université de Montreal, Faculté de Médecine, Montreal, Quebec, Canada.
authors: Marie
authors: M
authors: Trudel
authors: Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA fqian@medicine.umaryland.edu.
authors: Feng
authors: F
authors: Qian
mesh_terms: D000818:Animals; D001665:Binding Sites; D001693:Biological Transport, Active; D002462:Cell Membrane / Q000378:metabolism; D005816:Genetic Complementation Test; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D050396:TRPP Cation Channels