{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:54:34Z","timestamp":1792504474415,"version":"4.5.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2015,10,8]],"date-time":"2015-10-08T00:00:00Z","timestamp":1444262400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,10,8]],"date-time":"2015-10-08T00:00:00Z","timestamp":1444262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Primary cilia are antenna-like structures projected from the apical surface of various mammalian cells including renal tubular cells. Functional or structural defects of the cilium lead to systemic disorders comprising polycystic kidneys as a key feature. Here we show that anoctamin 6 (ANO6), a member of the anoctamin chloride channel family, is localized in the primary cilium of renal epithelial cells <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. ANO6 was not essential for cilia formation and had no effect on <jats:italic>in vitro<\/jats:italic> cyst expansion. However, knockdown of ANO6 impaired cyst lumen formation of MDCK cells in three-dimensional culture. In the absence of ANO6, apoptosis was reduced and epithelial cells were incompletely removed from the center of cell aggregates, which form in the early phase of cystogenesis. In line with these data, we show that ANO6 is highly expressed in apoptotic cyst epithelial cells of human polycystic kidneys. These data identify ANO6 as a cilium-associated protein and suggest its functional relevance in cyst formation.<\/jats:p>","DOI":"10.1038\/cddis.2015.273","type":"journal-article","created":{"date-parts":[[2015,10,8]],"date-time":"2015-10-08T12:46:14Z","timestamp":1444308374000},"page":"e1899-e1899","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Anoctamin 6 is localized in the primary cilium of renal tubular cells and is involved in apoptosis-dependent cyst lumen formation"],"prefix":"10.1038","volume":"6","author":[{"given":"V","family":"Forschbach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Goppelt-Struebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Kunzelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Schreiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Piedagnel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Kraus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K-U","family":"Eckardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Buchholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,8]]},"reference":[{"key":"BFcddis2015273_CR1","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1146\/annurev.physiol.69.040705.141236","volume":"69","author":"P Satir","year":"2007","unstructured":"Satir P, Christensen ST . Overview of structure and function of mammalian cilia. Annu Rev Physiol 2007; 69: 377\u2013400.","journal-title":"Annu Rev Physiol"},{"key":"BFcddis2015273_CR2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/2046-2530-2-6","volume":"2","author":"SG Basten","year":"2013","unstructured":"Basten SG, Giles RH . Functional aspects of primary cilia in signaling, cell cycle and tumorigenesis. Cilia 2013; 2: 6.","journal-title":"Cilia"},{"key":"BFcddis2015273_CR3","doi-asserted-by":"crossref","unstructured":"Hildebrandt F, Benzing T, Katsanis N . Ciliopathies. N Engl J Med 2011: 1533\u20131543.","DOI":"10.1056\/NEJMra1010172"},{"key":"BFcddis2015273_CR4","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s00424-011-0975-9","volume":"462","author":"K Kunzelmann","year":"2011","unstructured":"Kunzelmann K, Tian Y, Martins JR, Faria D, Kongsuphol P, Ousingsawat J et al. Anoctamins. Pflugers Archiv 2011; 462: 195\u2013208.","journal-title":"Pflugers Archiv"},{"key":"BFcddis2015273_CR5","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1152\/physrev.00039.2011","volume":"94","author":"N Pedemonte","year":"2014","unstructured":"Pedemonte N, Galietta LJ . Structure and function of TMEM16 proteins (anoctamins). Physiol Rev 2014; 94: 419\u2013459.","journal-title":"Physiol Rev"},{"key":"BFcddis2015273_CR6","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1159\/000366313","volume":"34","author":"C Iosco","year":"2014","unstructured":"Iosco C, Cosentino C, Sirna L, Romano R, Cursano S, Mongia A et al. Anoctamin 1 is apically expressed on thyroid follicular cells and contributes to ATP- and calcium-activated iodide efflux. Cell Physiol Biochem 2014; 34: 966\u2013980.","journal-title":"Cell Physiol Biochem"},{"key":"BFcddis2015273_CR7","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1042\/BJ20130348","volume":"452","author":"P Scudieri","year":"2013","unstructured":"Scudieri P, Sondo E, Caci E, Ravazzolo R, Galietta LJ . TMEM16A-TMEM16B chimaeras to investigate the structure-function relationship of calcium-activated chloride channels. Biochem J 2013; 452: 443\u2013455.","journal-title":"Biochem J"},{"key":"BFcddis2015273_CR8","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1038\/nature07313","volume":"455","author":"YD Yang","year":"2008","unstructured":"Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS et al. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature 2008; 455: 1210\u20131215.","journal-title":"Nature"},{"key":"BFcddis2015273_CR9","doi-asserted-by":"publisher","first-page":"C748","DOI":"10.1152\/ajpcell.00228.2012","volume":"304","author":"T Shimizu","year":"2013","unstructured":"Shimizu T, Iehara T, Sato K, Fujii T, Sakai H, Okada Y . TMEM16F is a component of a Ca2+-activated Cl- channel but not a volume-sensitive outwardly rectifying Cl- channel. Am J Physiol Cell Physiol 2013; 304: C748\u2013C759.","journal-title":"Am J Physiol Cell Physiol"},{"key":"BFcddis2015273_CR10","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/nature09583","volume":"468","author":"J Suzuki","year":"2010","unstructured":"Suzuki J, Umeda M, Sims PJ, Nagata S . Calcium-dependent phospholipid scrambling by TMEM16F. Nature 2010; 468: 834\u2013838.","journal-title":"Nature"},{"key":"BFcddis2015273_CR11","doi-asserted-by":"publisher","first-page":"13305","DOI":"10.1074\/jbc.M113.457937","volume":"288","author":"J Suzuki","year":"2013","unstructured":"Suzuki J, Fujii T, Imao T, Ishihara K, Kuba H, Nagata S . Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members. J Biol Chem 2013; 288: 13305\u201313316.","journal-title":"J Biol Chem"},{"key":"BFcddis2015273_CR12","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1007\/s00424-013-1305-1","volume":"466","author":"K Kunzelmann","year":"2014","unstructured":"Kunzelmann K, Nilius B, Owsianik G, Schreiber R, Ousingsawat J, Sirianant L et al. Molecular functions of anoctamin 6 (TMEM16F): a chloride channel, cation channel, or phospholipid scramblase? Pflugers Archiv 2014; 466: 407\u2013414.","journal-title":"Pflugers Archiv"},{"key":"BFcddis2015273_CR13","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1038\/ki.2013.418","volume":"85","author":"B Buchholz","year":"2014","unstructured":"Buchholz B, Faria D, Schley G, Schreiber R, Eckardt KU, Kunzelmann K . Anoctamin 1 induces calcium-activated chloride secretion and proliferation of renal cyst-forming epithelial cells. Kidney Int 2014; 85: 1058\u20131067.","journal-title":"Kidney Int"},{"key":"BFcddis2015273_CR14","doi-asserted-by":"publisher","first-page":"R126","DOI":"10.1016\/j.cub.2010.12.003","volume":"21","author":"A Datta","year":"2011","unstructured":"Datta A, Bryant DM, Mostov KE . Molecular regulation of lumen morphogenesis. Curr Biol 2011; 21: R126\u2013R136.","journal-title":"Curr Biol"},{"key":"BFcddis2015273_CR15","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1016\/j.bbadis.2011.01.006","volume":"1812","author":"B Goilav","year":"2011","unstructured":"Goilav B . Apoptosis in polycystic kidney disease. Biochim Biophys Acta 2011; 1812: 1272\u20131280.","journal-title":"Biochim Biophys Acta"},{"key":"BFcddis2015273_CR16","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1038\/ki.1995.186","volume":"47","author":"D Pri\u00e9","year":"1995","unstructured":"Pri\u00e9 D, Friedlander G, Coureau C, Vandewalle A, Cassing\u00e9na R, Ronco PM . Role of adenosine on glucagon-induced cAMP in a human cortical collecting duct cell line. Kidney Int 1995; 47: 1310\u20131318.","journal-title":"Kidney Int"},{"key":"BFcddis2015273_CR17","doi-asserted-by":"publisher","first-page":"e43584","DOI":"10.1371\/journal.pone.0043584","volume":"7","author":"C Keller","year":"2012","unstructured":"Keller C, Kroening S, Zuehlke J, Kunath F, Krueger B, Goppelt-Struebe M . Distinct mesenchymal alterations in N-cadherin and E-cadherin positive primary renal epithelial cells. PLoS One 2012; 7: e43584.","journal-title":"PLoS One"},{"key":"BFcddis2015273_CR18","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1681\/ASN.V13278","volume":"1","author":"R Mangoo-Karim","year":"1990","unstructured":"Mangoo-Karim R, Grantham JJ . Transepithelial water permeability in an in vitro model of renal cysts. J Am Soc Nephrol 1990; 1: 278\u2013285.","journal-title":"J Am Soc Nephrol"},{"key":"BFcddis2015273_CR19","doi-asserted-by":"publisher","first-page":"e92749","DOI":"10.1371\/journal.pone.0092749","volume":"9","author":"P Zhao","year":"2014","unstructured":"Zhao P, Torcaso A, Mariano A, Xu L, Mohsin S, Zhao L et al. Anoctamin 6 regulates C2C12 myoblast proliferation. PLoS One 2014; 9: e92749.","journal-title":"PLoS One"},{"key":"BFcddis2015273_CR20","doi-asserted-by":"publisher","first-page":"e611","DOI":"10.1038\/cddis.2013.135","volume":"4","author":"A Kmit","year":"2013","unstructured":"Kmit A, van Kruchten R, Ousingsawat J, Mattheij NJ, Senden-Gijsbers B, Heemskerk JW et al. Calcium-activated and apoptotic phospholipid scrambling induced by Ano6 can occur independently of Ano6 ion currents. Cell Death Dis 2013; 4: e611.","journal-title":"Cell Death Dis"},{"key":"BFcddis2015273_CR21","doi-asserted-by":"publisher","first-page":"6169","DOI":"10.1073\/pnas.95.11.6169","volume":"95","author":"I Szabo","year":"1998","unstructured":"Szabo I, Lepple-Wienhues A, Kaba KN, Zoratti M, Gulbins E, Lang F . Tyrosine kinase-dependent activation of a chloride channel in CD95-induced apoptosis in T lymphocytes. Proc Natl Acad Sci USA 1998; 95: 6169\u20136174.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2015273_CR22","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1182\/blood-2012-09-454314","volume":"121","author":"R van Kruchten","year":"2013","unstructured":"van Kruchten R, Mattheij NJ, Saunders C, Feijge MA, Swieringa F, Wolfs JL et al. Both TMEM16F-dependent and TMEM16F-independent pathways contribute to phosphatidylserine exposure in platelet apoptosis and platelet activation. Blood 2013; 121: 1850\u20131857.","journal-title":"Blood"},{"key":"BFcddis2015273_CR23","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1083\/jcb.201111063","volume":"198","author":"Y Qi","year":"2012","unstructured":"Qi Y, Tian X, Liu J, Han Y, Graham AM, Simon MC et al. Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis. J Cell Biol 2012; 198: 103\u2013114.","journal-title":"J Cell Biol"},{"key":"BFcddis2015273_CR24","doi-asserted-by":"publisher","first-page":"6954","DOI":"10.1073\/pnas.0408518102","volume":"102","author":"Y Tao","year":"2005","unstructured":"Tao Y, Kim J, Faubel S, Wu JC, Sa Falk, Schrier RW et al. Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease. Proc Natl Acad Sci USA 2005; 102: 6954\u20136959.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2015273_CR25","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1038\/nature12833","volume":"504","author":"M Delling","year":"2013","unstructured":"Delling M, DeCaen PG, Doerner JF, Febvay S, Clapham DE . Primary cilia are specialized calcium signalling organelles. Nature 2013; 504: 311\u2013314.","journal-title":"Nature"},{"key":"BFcddis2015273_CR26","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/2046-2530-1-4","volume":"1","author":"YC Hsiao","year":"2012","unstructured":"Hsiao YC, Tuz K, Ferland RJ . Trafficking in and to the primary cilium. Cilia 2012; 1: 4.","journal-title":"Cilia"},{"key":"BFcddis2015273_CR27","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1091\/mbc.e13-10-0599","volume":"25","author":"CC Ruppersburg","year":"2014","unstructured":"Ruppersburg CC, Hartzell HC . The Ca2+-activated Cl- channel ANO1\/TMEM16A regulates primary ciliogenesis. Mol Biol Cell 2014; 25: 1793\u20131807.","journal-title":"Mol Biol Cell"},{"key":"BFcddis2015273_CR28","doi-asserted-by":"publisher","first-page":"e62165","DOI":"10.1371\/journal.pone.0062165","volume":"8","author":"C Boehlke","year":"2013","unstructured":"Boehlke C, Kotsis F, Buchholz B, Powelske C, Eckardt K-u, Walz G et al. Kif3a Guides Microtubular Dynamics, Migration and Lumen Formation of MDCK Cells. PLoS One 2013; 8: e62165.","journal-title":"PLoS One"},{"key":"BFcddis2015273_CR29","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1007\/s00424-013-1428-4","volume":"466","author":"CA Juul","year":"2014","unstructured":"Juul CA, Grubb S, Poulsen KA, Kyed T, Hashem N, Lambert IH et al. Anoctamin 6 differs from VRAC and VSOAC but is involved in apoptosis and supports volume regulation in the presence of Ca2+. Pflugers Archiv 2014; 466: 1899\u20131910.","journal-title":"Pflugers Archiv"},{"key":"BFcddis2015273_CR30","doi-asserted-by":"publisher","first-page":"18168","DOI":"10.1073\/pnas.1108094108","volume":"108","author":"JR Martins","year":"2011","unstructured":"Martins JR, Faria D, Kongsuphol P, Reisch B, Schreiber R, Kunzelmann K . Anoctamin 6 is an essential component of the outwardly rectifying chloride channel. Proc Natl Acad Sci USA 2011; 108: 18168\u201318172.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2015273_CR31","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1042\/BST20120345","volume":"41","author":"CR Lenihan","year":"2013","unstructured":"Lenihan CR, Taylor CT . The impact of hypoxia on cell death pathways. Biochem Soc Trans 2013; 41: 657\u2013663.","journal-title":"Biochem Soc Trans"},{"key":"BFcddis2015273_CR32","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1681\/ASN.2013030209","volume":"25","author":"B Buchholz","year":"2014","unstructured":"Buchholz B, Schley G, Faria D, Kroening S, Willam C, Schreiber R et al. Hypoxia-inducible factor-1alpha causes renal cyst expansion through calcium-activated chloride secretion. J Am Soc Nephrol 2014; 25: 465\u2013474.","journal-title":"J Am Soc Nephrol"},{"key":"BFcddis2015273_CR33","doi-asserted-by":"publisher","first-page":"e207","DOI":"10.1182\/blood-2010-10-314427","volume":"117","author":"J Sch\u00f6del","year":"2011","unstructured":"Sch\u00f6del J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR . High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood 2011; 117: e207\u2013e217.","journal-title":"Blood"},{"key":"BFcddis2015273_CR34","first-page":"6669","volume":"61","author":"HM Sowter","year":"2001","unstructured":"Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL . HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 2001; 61: 6669\u20136673.","journal-title":"Cancer Res"},{"key":"BFcddis2015273_CR35","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1038\/sj.ki.5000062","volume":"69","author":"WM Bernhardt","year":"2006","unstructured":"Bernhardt WM, Schmitt R, Rosenberger C, M\u00fcnchenhagen PM, Gr\u00f6ne H-J, Frei U et al. Expression of hypoxia-inducible transcription factors in developing human and rat kidneys. Kidney Int 2006; 69: 114\u2013122.","journal-title":"Kidney Int"},{"key":"BFcddis2015273_CR36","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/s00109-010-0715-1","volume":"89","author":"B Buchholz","year":"2011","unstructured":"Buchholz B, Teschemacher B, Schley G, Schillers H, Eckardt KU . Formation of cysts by principal-like MDCK cells depends on the synergy of cAMP- and ATP-mediated fluid secretion. J Mol Med 2011; 89: 251\u2013261.","journal-title":"J Mol Med"},{"key":"BFcddis2015273_CR37","doi-asserted-by":"crossref","unstructured":"Schley G, Scholz H, Kraus A, Hackenbeck T, Klanke B, Willam C et al. Hypoxia inhibits nephrogenesis through paracrine Vegfa despite the ability to enhance tubulogenesis. Kidney Int 2015; e-pub ahead of print 22 July 2015; doi:10.1038\/ki.2015.214.","DOI":"10.1038\/ki.2015.214"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2015273.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2015273","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2015273.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T10:14:24Z","timestamp":1672913664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2015273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,8]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2015,10]]}},"alternative-id":["BFcddis2015273"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2015.273","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,8]]},"assertion":[{"value":"30 April 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2015","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 2015","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}