Polycystin-1 negatively regulates Polycystin-2 expression via the aggresome/autophagosome pathway.
Mutations of the PKD1 and PKD2 genes, encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively, lead to autosomal dominant polycystic kidney disease. Interestingly, up-regulation or down-regulation of PKD1 or PKD2 leads to polycystic kidney disease in animal models, but their interrelations are not completely understood. We show here that full-length PC1 that interacts with PC2 via a C-terminal coiled-coil domain regulates PC2 expression in vivo and in vitro by down-regulating PC2 expression in a dose-dependent manner. Expression of the pathogenic mutant R4227X, which lacks the C-terminal coiled-coil domain, failed to down-regulate PC2 expression, suggesting that PC1-PC2 interaction is necessary for PC2 regulation. The proteasome and autophagy are two pathways that control protein degradation. Proteins that are not degraded by proteasomes precipitate in the cytoplasm and are transported via histone deacetylase 6 (HDAC6) toward the aggresomes. We found that HDAC6 binds to PC2 and that expression of full-length PC1 accelerates the transport of the HDAC6-PC2 complex toward aggresomes, whereas expression of the R4227X mutant fails to do so. Aggresomes are engulfed by autophagosomes, which then fuse with the lysosome for degradation; this process is also known as autophagy. We have now shown that PC1 overexpression leads to increased degradation of PC2 via autophagy. Interestingly, PC1 does not activate autophagy generally. Thus, we have now uncovered a new pathway suggesting that when PC1 is expressed, PC2 that is not bound to PC1 is directed to aggresomes and subsequently degraded via autophagy, a control mechanism that may play a role in autosomal dominant polycystic kidney disease pathogenesis.
Division of Nephrology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Valeriu
V
Cebotaru
Departments of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Liudmila
L
Cebotaru
Division of Nephrology, Departments of Medicine, University of Maryland, Baltimore, Maryland 21201.
Hyunho
H
Kim
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
Marco
M
Chiaravalli
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
Alessandra
A
Boletta
Division of Nephrology, Departments of Medicine, University of Maryland, Baltimore, Maryland 21201.
Feng
F
Qian
Departments of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. Electronic address: wguggino@jhmi.edu.
William B
WB
Guggino
D000818:Animals; D001343:Autophagy; D004285:Dogs; D015536:Down-Regulation; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D053858:Metabolic Networks and Pathways; D051379:Mice; D010588:Phagosomes; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism; D050396:TRPP Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D050396:TRPP Cation Channels; C499033:Hdac6 protein, mouse
Calcium Channels; Physiology; Protein Degradation; Protein Processing; Trafficking