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Polycystin-2 and Phosphodiesterase 4C Are Components of a Ciliary A-Kinase Anchoring Protein Complex That Is Disrupted in Cystic Kidney Diseases

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Polycystin-2 and Phosphodiesterase 4C Are Components of a Ciliary A-Kinase Anchoring Protein Complex That Is Disrupted in Cystic Kidney Diseases Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases Yun-Hee Choia,1, Akira Suzukia,1, Sachin Hajarnisa, Zhendong Maa, Hannah C. Chapinb, Michael J. Caplanb, Marco Pontoglioc, Stefan Somlod, and Peter Igarashia,e,2 Departments of aInternal Medicine and ePediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390; Departments of bCellular and Molecular Physiology and dInternal Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06520; and cInstitut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université Paris-Descartes, Institut Cochin, 75014 Paris, France Edited* by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved May 23, 2011 (received for review October 28, 2010) Polycystic kidney disease (PKD) is a genetic disorder that is primary cilia have an abnormality in planar cell polarity that may characterized by cyst formation in kidney tubules. PKD arises from initiate cyst formation (7). Primary cilia have been shown to abnormalities of the primary cilium, a sensory organelle located on regulate several intracellular signaling pathways that control the cell surface. Here, we show that the primary cilium of renal planar cell polarity, including Wnt/β-catenin signaling (8, 9); epithelial cells contains a protein complex comprising adenylyl however, the mechanism by which the loss of renal cilia produces cyclase 5/6 (AC5/6), A-kinase anchoring protein 150 (AKAP150), kidney cysts remains poorly understood. and protein kinase A. Loss of primary cilia caused by deletion of The intracellular second messenger cAMP has been implicated Kif3a results in activation of AC5 and increased cAMP levels. Polycystin-2 in the growth and expansion of kidney cysts (10). Renal cAMP (PC2), a ciliary calcium channel that is mutated in human PKD, concentrations are elevated in animal models of PKD (8). interacts with AC5/6 through its C terminus. Deletion of PC2 Treatment of embryonic kidney explants from Pkd1 mutant mice increases cAMP levels, which can be corrected by reexpression of with 8-Br-cAMP results in tubular dilation (11). Moreover, cAMP wild-type PC2 but not by a mutant lacking calcium channel activity. increases the proliferation of ADPKD cyst epithelial cells by ac- MEDICAL SCIENCES Phosphodiesterase 4C (PDE4C), which catabolizes cAMP, is also tivating the B-Raf/MEK/ERK pathway (12). This effect appears located in renal primary cilia and interacts with the AKAP150 com- to be Ca2+ dependent because treatment with Ca2+ ionophores plex. Expression of PDE4C is regulated by the transcription factor inhibits the mitogenic response to cAMP, whereas Ca2+ channel hepatocyte nuclear factor-1β (HNF-1β), mutations of which pro- blockers promote proliferation (10). Subcellular compartmen- duce kidney cysts. PDE4C is down-regulated and cAMP levels are talization of cAMP signaling is mediated by A-kinase anchoring increased in HNF-1β mutant kidney cells and mice. Collectively, proteins (AKAP), which tether adenylyl cyclases (AC) that syn- these findings identify PC2 and PDE4C as unique components of thesize cAMP with downstream effectors such as protein kinase an AKAP complex in primary cilia and reveal a common mechanism A (PKA), phosphodiesterases (PDE), and exchange factors di- for dysregulation of cAMP signaling in cystic kidney diseases aris- rectly activated by cAMP (Epac) (13). Receptor-mediated ago- ing from different gene mutations. nists of adenylyl cyclase or nonselective phosphodiesterase inhibitors increase cAMP levels in cyst epithelial cells and stim- cyclic AMP | PKD2 | vHNF1 | TCF2 | intraflagellar transport ulate fluid secretion and proliferation (14, 15). Conversely, drugs that inhibit cAMP synthesis reduce cyst formation in animal olycystic kidney disease (PKD) is the most common genetic models and are currently being evaluated in clinical trials of hu- Pcause of kidney failure in humans (1). PKD is characterized man ADPKD (16). However, the mechanism that is responsible by kidney enlargement and progressive loss of renal function due for the elevation of cAMP levels in PKD is not known. to the accumulation of numerous fluid-filled cysts in the renal parenchyma. The cysts arise from renal tubules as a consequence Results of disturbances in cell proliferation, apoptosis, differentiation, Loss of Primary Cilia Activates cAMP Signaling. To investigate the fluid secretion, and planar cell polarity (2). The autosomal role of the primary cilium in the regulation of cAMP signaling, dominant form of PKD (ADPKD) is caused by mutations of we generated renal epithelial cell lines lacking primary cilia. Kif3aF/– fl PKD1 or PKD2, which encode the membrane proteins polycystin-1 mice carrying one null allele and one oxed allele of Kif3a (PC1) and polycystin-2 (PC2), respectively (3). PC1 and PC2 are the ciliogenic gene were crossed with mice expressing localized in the primary cilium, a whip-like, sensory organelle temperature-sensitive mutant SV40 large T antigen, and condi- that projects from the surface of most cells (1, 2). In the kidney, tionally immortalized renal epithelial cell lines were established. Kif3a Kif3aF/– primary cilia are located on the apical surface of renal tubular To delete , cells were infected with a retrovirus Kif3a−/− epithelial cells and project into the tubule lumen. Renal cilia are encoding self-excising Cre recombinase. The resulting immotile but bend in response to fluid flow and may have a mechanosensory function (4). In addition to PKD, several other human genetic disorders, collectively called the ciliopathies, are Author contributions: Y.-H.C., A.S., Z.M., and P.I. designed research; Y.-H.C., A.S., S.H., Z.M., H.C.C., and M.J.C. performed research; M.P. and S.S. contributed new reagents/ caused by mutations in proteins that are localized in the primary analytic tools; Y.-H.C., S.H., Z.M., and P.I. analyzed data; and Y.-H.C., A.S., S.H., and P.I. cilium and/or basal body (5). wrote the paper. The synthesis and maintenance of primary cilia requires The authors declare no conflict of interest. fl intra agellar transport, in which multiprotein complexes are *This Direct Submission article had a prearranged editor. transported along the ciliary axoneme by kinesin-II and dynein 1Y.-H.C. and A.S. contributed equally to this work. fi motor proteins. We have previously shown that kidney-speci c 2To whom correspondence should be addressed. E-mail: peter.igarashi@utsouthwestern. inactivation of the KIF3A subunit of kinesin-II results in the loss edu. of renal cilia and produces kidney cysts in mice (6). Analysis of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. precystic tubules in Kif3a mutant mice revealed that cells lacking 1073/pnas.1016214108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1016214108 PNAS Early Edition | 1of6 Downloaded by guest on October 2, 2021 cells lacked KIF3A protein and primary cilia, whereas cilia were phosphorylated PKA substrates (RRXXS/T) revealed increased – present on the parental Kif3aF/ cells (Fig. 1A and Fig. S1 A–C). staining in the nuclei of cyst epithelial cells compared with the – − − Compared with Kif3aF/ cells, Kif3a / cells contained higher levels predominantly cytoplasmic staining in wild-type renal tubules of cAMP under basal conditions and following treatment with (Fig. 1F). As a positive control, staining was also increased in − − – forskolin, a diterpene that maximally activates adenylyl cyclases cultured Kif3a / cells compared with Kif3aF/ cells (Fig. S1D). (Fig. 1B). The increase in cAMP levels was sufficient to activate Similarly, staining with an antibody against phospho-CREB, a cAMP-dependent signaling, as indicated by cAMP response ele- specific PKA substrate, showed increased nuclear staining in − − ment binding protein (CREB) reporter assays (Fig. 1C). Kif3a / kidney cysts (Fig. 1G). Costaining with fluorescent lectins cells also exhibited enhanced phosphorylation of the PKA sub- showed that cAMP signaling was activated in cysts derived from strate Kemptide (Fig. 1 D and E). both proximal tubules and collecting ducts (Fig. 1 F and G). In addition to primary cilia, KIF3A is also located in the cy- toplasm where it may have other functions (Fig. S1C). To verify AC5/6 and AKAP150 Are Localized in Renal Primary Cilia. cAMP is that the effects on cAMP were due to the loss of primary cilia, synthesized by adenylyl cyclase, which comprises a family of nine – ciliated Kif3aF/ cells were deciliated with dibucaine (17). Treat- membrane-associated isoenzymes with distinct tissue distribu- ment with dibucaine resulted in the removal of cilia from ∼95% tions and subcellular localizations. Adenylyl cyclase 6 (AC6) has of cells (Fig. S1 E and F) and increased cAMP levels (Fig. S1G). previously been localized in primary cilia in renal tubular cells – As a negative control, dibucaine had no effect on the already and cholangiocytes (19, 20). In Kif3aF/ renal epithelial cells, − − elevated cAMP levels in nonciliated Kif3a / cells. Because the adenylyl cyclases 5 and 6 (AC5/6) colocalized with acetylated − − formation of primary cilia depends on cell confluence (18), we tubulin, a marker of the primary cilium (Fig. 2A). In Kif3a / also compared cAMP levels in confluent and nonconfluent cells. cells, cilia were absent, and AC5/6 remained associated with the cAMP levels were higher in nonconfluent
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