Bicc1 links the regulation of cAMP signaling in polycystic kidneys to microRNA-induced gene silencing.
Genetic defects in autosomal-dominant polycystic kidney disease (ADPKD) promote cystic growth of renal tubules, at least in part by stimulating the accumulation of cAMP. How renal cAMP levels are regulated is incompletely understood. We show that cAMP and the expression of its synthetic enzyme adenylate cyclase-6 (AC6) are up-regulated in cystic kidneys of Bicc1(-)(/-) knockout mice. Bicc1, a protein comprising three K homology (KH) domains and a sterile alpha motif (SAM), is expressed in proximal tubules. The KH domains independently bind AC6 mRNA and recruit the miR-125a from Dicer, whereas the SAM domain enables silencing by Argonaute and TNRC6A/GW182. Bicc1 similarly induces silencing of the protein kinase inhibitor PKIα by miR-27a. Thus, Bicc1 is needed on these target mRNAs for silencing by specific miRNAs. The repression of AC6 by Bicc1 might explain why cysts in ADPKD patients preferentially arise from distal tubules.
Ecole Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19, CH-1015 Lausanne,  Switzerland.
Nathalie
N
Piazzon
Charlotte
C
Maisonneuve
Isabelle
I
Guilleret
Samuel
S
Rotman
Daniel B
DB
Constam
D020413:3' Untranslated Regions / Q000235:genetics; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D020413:3' Untranslated Regions; C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; C540667:Bicc1 protein, mouse; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; C107593:Pkia protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6