Advanced search
Publication Cover
Autophagy Volume 19, 2023 - Issue 1
Submit an article Journal homepage
4,171
Views
3
CrossRef citations to date
0
Altmetric
Review

Crosstalk between cilia and autophagy: implication for human diseases

Manuela Morleoa Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy;b Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, ItalyORCID Iconhttps://orcid.org/0000-0002-7553-3245View further author information
ORCID Icon,
Helena L.A. Vieirac CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa1169-056, Portugal;d UCIBIO, Applied Molecular Biosciences Unit, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica, Portugal;e Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica, PortugalView further author information
,
Petra Pennekampf Department of General Pediatrics, University Hospital Münster, University of Münster, Münster48149, Germany;g Member of the European Reference Networks ERN-LUNG, Lisbon, PortugalView further author information
,
Alessandro Palmah Department of Onco-hematology, Gene and Cell Therapy, Bambino Gesù Children’s Hospital - IRCCS, Rome, ItalyView further author information
,
Liliana Bento-Lopesc CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa1169-056, PortugalView further author information
,
Heymut Omranf Department of General Pediatrics, University Hospital Münster, University of Münster, Münster48149, Germany;g Member of the European Reference Networks ERN-LUNG, Lisbon, PortugalView further author information
,
Susana S. Lopesc CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa1169-056, Portugal;g Member of the European Reference Networks ERN-LUNG, Lisbon, PortugalView further author information
,
Duarte C. Barralc CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa1169-056, PortugalView further author information
&
Brunella Francoa Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy;i Medical Genetics, Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy;j Scuola Superiore Meridionale, School for Advanced Studies, Naples, ItalyCorrespondence[email protected]
View further author information
 show all
Pages 24-43 | Received 17 Oct 2021, Accepted 13 Apr 2022, Published online: 25 May 2022

References

  • Mizushima N. A brief history of autophagy from cell biology to physiology and disease. Nat Cell Biol. 2018;20(5):521–527.
  • He LQ, Lu JH, Yue ZY. Autophagy in ageing and ageing-associated diseases. Acta Pharmacol Sin. 2013;34(5):605–611.
  • Jiang P, Mizushima N. Autophagy and human diseases. Cell Res. 2014;24(1):69–79.
  • Stamatakou E, Wróbel L, Hill SM, et al. Mendelian neurodegenerative disease genes involved in autophagy. Cell Discov. 2020;6(1):24. DOI:10.1038/s41421-020-0158-y.
  • Klionsky DJ, Eskelinen E-L, Deretic V. Autophagosomes, phagosomes, autolysosomes, phagolysosomes, autophagolysosomes … wait, I’m confused. Autophagy. 2014;10(4):549–551.
  • Duve de C. Lysosomes revisited. Eur J Biochem. 1983;137(3):391–397.
  • Melia TJ, Lystad AH, Simonsen A. Autophagosome biogenesis: from membrane growth to closure. J Cell Biol. 2020;219(6):e202002085.
  • Condon KJ, Sabatini DM. Nutrient regulation of mTORC1 at a glance. J Cell Sci. 2019;132(21):0–2.
  • King KE, Losier TT, Russell RC. Regulation of autophagy enzymes by nutrient signaling. Trends Biochem Sci. 2021;46(8):687–700.
  • Johansen T, Lamark T. Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors. J Mol Biol. 2020;432(1):80–103.
  • Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014;16(6):495–501.
  • Gubas A, Dikic I. A guide to the regulation of selective autophagy receptors. FEBS J. 2022;289(1):75–89.
  • Satir P, Heuser T, Sale WS, et al. Basis for How Motile Cilia Beat. Bioscience. 2014;64(12):1073–1083.
  • Woolley DM. Flagellar oscillation: a commentary on proposed mechanisms. Biol Rev Camb Philos Soc. 2010;85(3):453–470.
  • Aprea I, Nöthe-Menchen T, Dougherty GW, et al. Motility of efferent duct cilia aids passage of sperm cells through the male reproductive system. Mol Hum Reprod. 2021;27(3):gaab009. DOI:10.1093/molehr/gaab009.
  • Little RB, Norris DP. Right, left and cilia: how asymmetry is established. Semin Cell Dev Biol. 2021;110:11–18.
  • Kobayashi T, Dynlacht BD. Regulating the transition from centriole to basal body. J Cell Biol. 2011;193(3):435–444.
  • Conduit PT, Wainman A, Raff JW. Centrosome function and assembly in animal cells. Nat Rev Mol Cell Biol. 2015;16(10):611–624.
  • Gonçalves J, Pelletier L. The Ciliary Transition Zone: finding the Pieces and Assembling the Gate. Mol Cells. 2017;40(4):243–253.
  • Ishikawa H, Marshall WF. Intraflagellar Transport and Ciliary Dynamics. Cold Spring Harb Perspect Biol. 2017;9(3):a021998.
  • Shakya S, Westlake CJ. Recent advances in understanding assembly of the primary cilium membrane. Fac Rev. 2021;10:10.
  • Wang L, Dynlacht BD. The regulation of cilium assembly and disassembly in development and disease. Development. 2018;145(18):18.
  • Reiter JF, Leroux MR. Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol. 2017;18(9):533–547.
  • Bergmann C, Guay-Woodford LM, Harris PC, et al. Polycystic kidney disease. Nat Rev Dis Prim. 2018;4(1):50. DOI:10.1038/s41572-018-0047-y.
  • Franco B, Thauvin-Robinet C. Update on oral-facial-digital syndromes (OFDS). Cilia. 2016;5(1):12.
  • Morleo M, Franco B, Type OFD. I syndrome: lessons learned from a rare ciliopathy. Biochem Soc Trans. 2020;48(5):1929–1939.
  • Pezzella N, Bove G, Tammaro R, et al. OFD1: one gene, several disorders. Am J Med Genet C Semin Med Genet. 2022; Online ahead of print. DOI:10.1002/ajmg.c.31962.
  • Parisi MA. The molecular genetics of Joubert syndrome and related ciliopathies: the challenges of genetic and phenotypic heterogeneity. Trans Sci Rare Dis. 2019;4(1–2):25–49.
  • Barker AR, Thomas R, Dawe HR. Meckel-Gruber syndrome and the role of primary cilia in kidney, skeleton, and central nervous system development. Organogenesis. 2014;10(1):96–107.
  • Luijten MN, Basten SG, Claessens T, et al. Birt-Hogg-Dube syndrome is a novel ciliopathy. Hum Mol Genet. 2013;22(21):4383–4397. DOI:10.1016/j.cell.2019.10.036.
  • Braun DA, Hildebrandt F. Hildebrandt F. Ciliopathies. Cold Spring Harb Perspect Biol. 2017;9(3):a028191.
  • Cao M, Zhong Q. Cilia in autophagy and cancer. Cilia. 2015;5(1):4.
  • Yun C, Lee S. The Roles of Autophagy in Cancer. Int J Mol Sci. 2018;19(11):3466.
  • Wang B, Liang Z, Liu P. Functional aspects of primary cilium in signaling, assembly and microenvironment in cancer. J Cell Physiol. 2021;236(5):3207–3219.
  • Wallmeier J, Nielsen KG, Kuehni CE, et al. Motile ciliopathies. Nat Rev Dis Prim. 2020;6(1):77. DOI:10.1038/s41572-020-0209-6.
  • Franco B, Morleo M. The role of OFD1 in selective autophagy. Mol Cell Oncol. 2021;8(3):1903291.
  • Pampliega O, Cuervo AM. Autophagy and primary cilia: dual interplay. Curr Opin Cell Biol. 2016;39:1–7.
  • Morleo F. The Autophagy-Cilia Axis: an Intricate Relationship. Cells. 2019;8(8):905.
  • Yamamoto Y, Chino H, Tsukamoto S, et al. NEK9 regulates primary cilia formation by acting as a selective autophagy adaptor for MYH9/myosin IIA. Nat Commun. 2021;12(1):3292. DOI:10.1038/s41467-021-23599-7.
  • Tang Z, Lin MG, Stowe TR, et al. Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. Nature. 2013;502(7470):254–257. DOI:10.1038/nature12606.
  • Singla V, Romaguera-Ros M, Garcia-Verdugo JM, et al. Ofd1, a human disease gene, regulates the length and distal structure of centrioles. Dev Cell. 2010;18(3):410–424. DOI:10.1016/j.devcel.2009.12.022.
  • Ferrante MI, Zullo A, Barra A, et al. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet. 2006;38(1):112–117. DOI:10.1038/ng1684.
  • Pampliega O, Orhon I, Patel B, et al. Functional interaction between autophagy and ciliogenesis. Nature. 2013;502(7470):194–200. DOI:10.1038/nature12639.
  • Boukhalfa A, Miceli C, Ávalos Y, et al. Interplay between primary cilia, ubiquitin-proteasome system and autophagy. Biochimie. 2019;166:286–292.
  • Hubbert C, Guardiola A, Shao R, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417(6887):455–458. DOI:10.1038/417455a.
  • Lee J-Y, Koga H, Kawaguchi Y, et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 2010;29(5):969–980. DOI:10.1038/emboj.2009.405.
  • Lam HC, Cloonan SM, Bhashyam AR, et al. Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction. J Clin Invest. 2013;123(12):5212–5230. DOI:10.1172/JCI69636.
  • Spektor A, Tsang WY, Khoo D, et al. Cep97 and CP110 Suppress a Cilia Assembly Program. Cell. 2007;130(4):678–690. DOI:10.1016/j.cell.2007.06.027.
  • Bettencourt-Dias M, Carvalho-Santos Z. Double life of centrioles: CP110 in the spotlight. Trends Cell Biol. 2008;18(1):8–11.
  • Liu M, Zhang W, Li M, et al. NudCL2 is an autophagy receptor that mediates selective autophagic degradation of CP110 at mother centrioles to promote ciliogenesis. Cell Res. 2021;31(11):1199–1211. DOI:10.1038/s41422-021-00560-3.
  • Arora K, Lund JR, Naren NA, et al. AC6 regulates the microtubule-depolymerizing kinesin KIF19A to control ciliary length in mammals. J Biol Chem. 2020;295(42):14250–14259. DOI:10.1074/jbc.RA120.013703.
  • Leopold PL, O’Mahony MJ, Lian XJ, et al. Smoking is associated with shortened airway cilia. PLoS One. 2009;4(12):e8157. DOI:10.1371/journal.pone.0008157.
  • Hessel J, Heldrich J, Fuller J, et al. Intraflagellar transport gene expression associated with short cilia in smoking and COPD. PLoS One. 2014;9(1):e85453. DOI:10.1371/journal.pone.0085453.
  • Bottier M, Thomas KA, Dutcher SK, et al. How Does Cilium Length Affect Beating? Biophys J. 2019;116(7):1292–1304. DOI:10.1016/j.bpj.2019.02.012.
  • Pintado P, Sampaio P, Tavares B, et al. Dynamics of cilia length in left–right development. R Soc Open Sci. 2017;4(3):161102. DOI:10.1098/rsos.161102.
  • Niwa S, Nakajima K, Miki H, et al. KIF19A Is a Microtubule-Depolymerizing Kinesin for Ciliary Length Control. Dev Cell. 2012;23(6):605–611. DOI:10.1016/j.devcel.2012.10.016.
  • Moore BS, Stepanchick AN, Tewson PH, et al. Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics. Proc Natl Acad Sci. 2016;113(46):549–551. DOI:10.1073/pnas.1602393113.
  • Besschetnova TY, Kolpakova-Hart E, Guan Y, et al. Identification of Signaling Pathways Regulating Primary Cilium Length and Flow-Mediated Adaptation. Curr Biol. 2010;20(2):182–187. DOI:10.1016/j.cub.2009.11.072.
  • Flaherty J, Feng Z, Peng Z, et al. Primary cilia have a length-dependent persistence length. Biomech Model Mechanobiol. 2020;19(2):445–460. DOI:10.1007/s10237-019-01220-7.
  • Volinia S, Dhand R, Vanhaesebroeck B, et al. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J. 1995;14(14):3339–3348. DOI:10.1002/j.1460-2075.1995.tb07340.x.
  • Lindmo K, Brech A, Finley KD, et al. The PI 3-kinase regulator Vps15 is required for autophagic clearance of protein aggregates. Autophagy. 2008;4(4):500–506. DOI:10.4161/auto.5829.
  • Stoetzel C, Bär S, Craene De J-O, et al. A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi. Nat Commun. 2016;7(1):13586. DOI:10.1038/ncomms13586.
  • Finetti F, Paccani SR, Rosenbaum J, et al. Intraflagellar transport: a new player at the immune synapse. Trends Immunol. 2011;32(4):139–145. DOI:10.1016/j.it.2011.02.001.
  • Boukhalfa A, Roccio F, Dupont N, et al. The autophagy protein ATG16L1 cooperates with IFT20 and INPP5E to regulate the turnover of phosphoinositides at the primary cilium. Cell Rep. 2021;35(4):109045. DOI:10.1016/j.celrep.2021.109045.
  • Boukhalfa A, Roccio F, Dupont N, et al. When the autophagy protein ATG16L1 met the ciliary protein IFT20. Autophagy. 2021;17(7):1791–1793. DOI:10.1080/15548627.2021.1935004.
  • Zemirli N, Boukhalfa A, Dupont N, et al. The primary cilium protein folliculin is part of the autophagy signaling pathway to regulate epithelial cell size in response to fluid flow. Cell Stress. 2019;3(3):100–109. DOI:10.15698/cst2019.03.180.
  • Orhon I, Dupont N, Zaidan M, et al. Primary-cilium-dependent autophagy controls epithelial cell volume in response to fluid flow. Nat Cell Biol. 2016;18(6):657–667. DOI:10.1038/ncb3360.
  • Xiang W, Jiang T, Hao X, et al. Primary cilia and autophagy interaction is involved in mechanical stress mediated cartilage development via ERK/mTOR axis. Life Sci. 2019;218:308–313.
  • Miceli C, Roccio F, Penalva-Mousset L, et al. The primary cilium and lipophagy translate mechanical forces to direct metabolic adaptation of kidney epithelial cells. Nat Cell Biol. 2020;22(9):1091–1102. DOI:10.1038/s41556-020-0566-0.
  • Miceli C, Roccio F, Penalva-Mousset L, et al. Fluid flow-induced shear stress controls the metabolism of proximal tubule kidney epithelial cells through primary cilium-dependent lipophagy and mitochondria biogenesis. Autophagy. 2020;16(12):2287–2288. DOI:10.1080/15548627.2020.1823125.
  • Jang J, Wang Y, Lalli MA, et al. Primary cilium-autophagy-Nrf2 (PAN) axis activation commits human embryonic stem cells to a neuroectoderm fate. Cell. 2016;165(2):410–420. DOI:10.1016/j.cell.2016.02.014.
  • Boehlke C, Kotsis F, Patel V, et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat Cell Biol. 2010;12(11):1115–1122. DOI:10.1038/ncb2117.
  • Boukhalfa A, Nascimbeni AC, Ramel D, et al. PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress. Nat Commun. 2020;11(1):294. DOI:10.1038/s41467-019-14086-1.
  • Franco I, Gulluni F, Campa CC, et al. PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. Dev Cell. 2014;28(6):647–658. DOI:10.1016/j.devcel.2014.01.022.
  • WuDunn D. Mechanobiology of trabecular meshwork cells. Exp Eye Res. 2009;88(4):718–723.
  • Shim MS, Nettesheim A, Hirt J, et al. The autophagic protein LC3 translocates to the nucleus and localizes in the nucleolus associated to NUFIP1 in response to cyclic mechanical stress. Autophagy. 2020;16(7):1248–1261. DOI:10.1080/15548627.2019.1662584.
  • Hirt J, Liton PB. Autophagy and mechanotransduction in outflow pathway cells. Exp Eye Res. 2017;158:146–153.
  • Morleo M, Brillante S, Formisano U, et al. Regulation of autophagosome biogenesis by OFD1mediated selective autophagy. EMBO J. 2021;40(4):4. DOI:10.15252/embj.2020105120.
  • Morleo M, Franco B. The OFD1 protein is a novel player in selective autophagy: another tile to the cilia/autophagy puzzle. Cell Stress. 2021;5(3):33–36.
  • Hoang-Minh LB, Deleyrolle LP, Nakamura NS, et al. PCM1 depletion inhibits glioblastoma cell ciliogenesis and increases cell death and sensitivity to temozolomide. Transl Oncol. 2016;9(5):392–402. DOI:10.1016/j.tranon.2016.08.006.
  • Keryer G, Pineda JR, Liot G, et al. Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J Clin Invest. 2011;121(11):4372–4382. DOI:10.1172/JCI57552.
  • Joachim J, Razi M, Judith D, et al. Centriolar satellites control GABARAP ubiquitination and GABARAP-mediated autophagy. Curr Biol. 2017;27(14):2123–2136 e7. DOI:10.1016/j.cub.2017.06.021.
  • Finetti F, Cassioli C, Cianfanelli V, et al. The intraflagellar transport protein IFT20 recruits ATG16L1 to early endosomes to promote autophagosome formation in T cells. Front Cell Dev Biol. 2021;9 :634003.
  • Liu ZQ, Lee JN, Son M, et al. Ciliogenesis is reciprocally regulated by PPARA and NR1H4/FXR through controlling autophagy in vitro and in vivo. Autophagy. 2018;14(6):1011–1027. DOI:10.1080/15548627.2018.1448326.
  • Kim ES, Shin JH, Park SJ, et al. Inhibition of autophagy suppresses sertraline-mediated primary ciliogenesis in retinal pigment epithelium cells. PLoS One. 2015;10(2):e0118190. DOI:10.1371/journal.pone.0118190.
  • Bao Z, Huang W. Thioridazine promotes primary ciliogenesis in lung cancer cells through enhancing cell autophagy. Int J Clin Exp Med. 2017;10(9):13960–13969.
  • Struchtrup A, Wiegering A, Stork B, et al. The ciliary protein RPGRIP1L governs autophagy independently of its proteasome-regulating function at the ciliary base in mouse embryonic fibroblasts. Autophagy. 2018;14(4):567–583. DOI:10.1080/15548627.2018.1429874.
  • Wang S, Livingston MJ, Su Y, et al. Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways. Autophagy. 2015;11(4):607–616. DOI:10.1080/15548627.2015.1023983.
  • Iaconis D, Crina C, Brillante S, et al. The HOPS complex subunit VPS39 controls ciliogenesis through autophagy. Hum Mol Genet. 2020;29(6):1018–1029. DOI:10.1093/hmg/ddaa029.
  • Gokey JJ, Dasgupta A, Amack JD. The V-ATPase accessory protein Atp6ap1b mediates dorsal forerunner cell proliferation and left–right asymmetry in zebrafish. Dev Biol. 2015;407(1):115–130.
  • Chen Y, Wu B, Xu L, et al. A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and in vivo. Cell Res. 2012;22(2):333–345. DOI:10.1038/cr.2011.134.
  • Kujala M, Hihnala S, Tienari J, et al. Expression of ion transport-associated proteins in human efferent and epididymal ducts. Reproduction. 2007;133(4):775–784. DOI:10.1530/rep.1.00964.
  • Finetti F, Cassioli C, Cianfanelli V, et al. The intraflagellar transport protein IFT20 controls lysosome biogenesis by regulating the post-Golgi transport of acid hydrolases. Cell Death Differ. 2020;27(1):310–328. DOI:10.1038/s41418-019-0357-y.
  • Dan Dunn J, Alvarez LAJ, Zhang X, et al. Reactive oxygen species and mitochondria: a nexus of cellular homeostasis. Redox Biol. 2015;6:472–485.
  • Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28(4):R170–85.
  • Sang L, Miller JJ, Corbit KC, et al. Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell. 2011;145(4):513–528. DOI:10.1016/j.cell.2011.04.019.
  • Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, et al. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet. 2011;43(8):776–784. DOI:10.1038/ng.891.
  • Williams CL, Li C, Kida K, et al. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol. 2011;192(6):1023–1041. DOI:10.1083/jcb.201012116.
  • Pike AN, Fisk HA. Centriole assembly and the role of Mps1: defensible or dispensable? Cell Div. 2011;6(1):9.
  • Majumder S, Fisk HA. VDAC3 and Mps1 negatively regulate ciliogenesis. Cell Cycle. 2013;12(5):849–858.
  • Majumder S, Cash A, Fisk H. Non-overlapping distributions and functions of the VDAC family in ciliogenesis. Cells. 2015;4(3):331–353.
  • Meyenberg Cunha-de Padua M, Fabbri L, Dufies M, et al. Evidences of a direct relationship between cellular fuel supply and ciliogenesis regulated by hypoxic VDAC1-ΔC. Cancers (Basel). 2020;12(11):3484. DOI:10.3390/cancers12113484.
  • Burkhalter MD, Sridhar A, Sampaio P, et al. Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis. J Clin Invest. 2019;129(7):2841–2855. DOI:10.1172/JCI98890.
  • Hofherr A, Seger C, Fitzpatrick F, et al. The mitochondrial transporter SLC25A25 links ciliary TRPP2 signaling and cellular metabolism. PLOS Biol. 2018;16(8):e2005651. DOI:10.1371/journal.pbio.2005651.
  • Bae J-E, Kang GM, Min SH, et al. Primary cilia mediate mitochondrial stress responses to promote dopamine neuron survival in a Parkinson’s disease model. Cell Death Dis. 2019;10(12):952. DOI:10.1038/s41419-019-2184-y.
  • Lee WR, Na H, Lee SW, et al. Transcriptomic analysis of mitochondrial TFAM depletion changing cell morphology and proliferation. Sci Rep. 2017;7(1):17841. DOI:10.1038/s41598-017-18064-9.
  • Orhon I, Dupont N, Pampliega O, et al. Autophagy and regulation of cilia function and assembly. Cell Death Differ. 2015;22(3):389–397. DOI:10.1038/cdd.2014.171.
  • Macca M, Franco B. The molecular basis of oral-facial-digital syndrome, type 1. Am J Med Genet C Semin Med Genet. 2009;151(4):318–325.
  • Zullo A, Iaconis D, Barra A, et al. Kidney-specific inactivation of Ofd1 leads to renal cystic disease associated with upregulation of the mTOR pathway. Hum Mol Genet. 2010;19(14):2792–2803. DOI:10.1093/hmg/ddq180.
  • Pazour GJ, San Agustin JT, Follit JA, et al. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr Biol. 2002;12(11):R378–80. DOI:10.1016/S0960-9822(02)00877-1.
  • Yoder BK, Hou X, Guay-Woodford LM. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol. 2002;13(10):2508–2516.
  • Nauli SM, Alenghat FJ, Luo Y, et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet. 2003;33(2):129–137. DOI:10.1038/ng1076.
  • Shillingford JM, Murcia NS, Larson CH, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A. 2006;103(14):5466–5471. DOI:10.1073/pnas.0509694103.
  • Boletta A. Emerging evidence of a link between the polycystins and the mTOR pathways. Pathogenetics. 2009;2(1):6.
  • Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):820–829. DOI:10.1056/NEJMoa0907419.
  • Kim HJ, Edelstein CL. Mammalian target of rapamycin inhibition in polycystic kidney disease: from bench to bedside. Kidney Res Clin Pr. 2012;31(3):132–138.
  • Cebotaru V, Cebotaru L, Kim H, et al. Polycystin-1 negatively regulates Polycystin-2 expression via the aggresome/autophagosome pathway. J Biol Chem. 2014;289(10):6404–6414. DOI:10.1074/jbc.M113.501205.
  • Peña-Oyarzun D, Rodriguez-Peña M, Burgos-Bravo F, et al. PKD2/polycystin-2 induces autophagy by forming a complex with BECN1. Autophagy. 2021;17(7):1714–1728. DOI:10.1080/15548627.2020.1782035.
  • Peintner L, Venkatraman A, Waeldin A, et al. Loss of PKD1/polycystin-1 impairs lysosomal activity in a CAPN (calpain)-dependent manner. Autophagy. 2021;17(9):2384–2400. DOI:10.1080/15548627.2020.1826716.
  • Peña-Oyarzun D, Batista-Gonzalez A, Kretschmar C, et al. New emerging roles of Polycystin-2 in the regulation of autophagy. Int Rev Cell Mol Biol. 2020;354:165–186.
  • Belibi F, Zafar I, Ravichandran K, et al. Hypoxia-inducible factor-1alpha (HIF-1alpha) and autophagy in polycystic kidney disease (PKD). Am J Physiol Ren Physiol. 2011;300(5):F1235–43. DOI:10.1152/ajprenal.00348.2010.
  • Rowe I, Chiaravalli M, Mannella V, et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med. 2013;19(4):488–493. DOI:10.1038/nm.3092.
  • Zhu P, Sieben CJ, Xu X, et al. Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model. Hum Mol Genet. 2017;26(1):158–172. DOI:10.1093/hmg/ddw376.
  • Ravichandran K, Edelstein CL. Polycystic kidney disease: a case of suppressed autophagy? Semin Nephrol. 2014;34(1):27–33.
  • Lim JS, Kim WI, Kang H-C-C, et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med. 2015;21(4):395–400. DOI:10.1038/nm.3824.
  • Park SM, Lim JS, Ramakrishina S, et al. Brain somatic mutations in MTOR disrupt neuronal ciliogenesis, leading to focal cortical dyslamination. Neuron. 2018;99(1):83–97 e7. DOI:10.1016/j.neuron.2018.05.039.
  • Slegtenhorst van M, Hoogt de R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277(5327):805–808. DOI:10.1126/science.277.5327.805.
  • The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75(7):1305–1315. DOI:10.1016/0092-8674(93)90618-Z.
  • Henske EP, Jóźwiak S, Kingswood JC, et al. Tuberous sclerosis complex. Nat Rev Dis Prim. 2016;2(1):16035. DOI:10.1038/nrdp.2016.35.
  • Slegtenhorst van M. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet. 1998;7(6):1053–1057.
  • Tee AR, Fingar DC, Manning BD, et al. Tuberous sclerosis complex-1 and −2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci. 2002;99(21):13571–13576. DOI:10.1073/pnas.202476899.
  • Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4(9):648–657. DOI:10.1038/ncb839.
  • Zhang J, Kim J, Alexander A, et al. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat Cell Biol. 2013;15(10):1186–1196. DOI:10.1038/ncb2822.
  • Papadakis M, Hadley G, Xilouri M, et al. Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy. Nat Med. 2013;19(3):351–357. DOI:10.1038/nm.3097.
  • Hartman TR, Liu D, Zilfou JT, et al. The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway. Hum Mol Genet. 2009;18(1):151–163. DOI:10.1093/hmg/ddn325.
  • DiBella LM, Park A, Sun Z. Zebrafish Tsc1reveals functional interactions between the cilium and the TOR pathway. Hum Mol Genet. 2009;18(4):595–606.
  • Rosengren T, Larsen LJ, Pedersen LB, et al. TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms. Cell Mol Life Sci. 2018;75(14):2663–2680. DOI:10.1007/s00018-018-2761-8.
  • Astrinidis A, Senapedis W, Henske EP. Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Hum Mol Genet. 2006;15(2):287–297.
  • Mallela K, Kumar A. Role of TSC1 in physiology and diseases. Mol Cell Biochem. 2021;476(6):2269–2282.
  • Di NA, Lenoël I, Winden KD, et al. Phenotypic screen with TSC-deficient neurons reveals heat-shock machinery as a druggable pathway for mTORC1 and reduced cilia. Cell Rep. 2020;31(12):107780. DOI:10.1016/j.celrep.2020.107780.
  • Bielas SL, Silhavy JL, Brancati F, et al. Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet. 2009;41(9):1032–1036. DOI:10.1038/ng.423.
  • Chavez M, Ena S, Sande Van J, et al. Modulation of ciliary phosphoinositide content regulates trafficking and sonic hedgehog signaling output. Dev Cell. 2015;34(3):338–350. DOI:10.1016/j.devcel.2015.06.016.
  • Garcia-Gonzalo FR, Phua SC, Roberson EC, et al. Phosphoinositides regulate ciliary protein trafficking to modulate hedgehog signaling. Dev Cell. 2015;34(4):400–409. DOI:10.1016/j.devcel.2015.08.001.
  • Hasegawa J, Iwamoto R, Otomo T, et al. Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with joubert syndrome. EMBO J. 2016;35(17):1853–1867. DOI:10.15252/embj.201593148.
  • Luo N, West CC, Murga-Zamalloa CA, et al. OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Hum Mol Genet. 2012;21(15):3333–3344. DOI:10.1093/hmg/dds163.
  • Conduit SE, Dyson JM, Mitchell CA. Inositol polyphosphate 5-phosphatases; new players in the regulation of cilia and ciliopathies. FEBS Lett. 2012;586(18):2846–2857.
  • Coon BG, Hernandez V, Madhivanan K, et al. The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. Hum Mol Genet. 2012;21(8):1835–1847. DOI:10.1093/hmg/ddr615.
  • Montjean R, Aoidi R, Desbois P, et al. OCRL-mutated fibroblasts from patients with dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells. Hum Mol Genet. 2015;24(4):994–1006. DOI:10.1093/hmg/ddu514.
  • Leo De MG, Staiano L, Vicinanza M, et al. Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL. Nat Cell Biol. 2016;18(8):839–850. DOI:10.1038/ncb3386.
  • Baba M, Hong S-B, Sharma N, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci. 2006;103(42):15552–15557. DOI:10.1073/pnas.0603781103.
  • Takagi Y, Kobayashi T, Shiono M, et al. Interaction of folliculin (birt-hogg-dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene. 2008;27(40):5339–5347. DOI:10.1038/onc.2008.261.
  • Petit CS, Roczniak-Ferguson A, Ferguson SM. Recruitment of folliculin to lysosomes supports the amino acid–dependent activation of rag GTPases. J Cell Biol. 2013;202(7):1107–1122.
  • Tsun ZY, Bar-Peled L, Chantranupong L, et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell. 2013;52(4):495–505. DOI:10.1016/j.molcel.2013.09.016.
  • Shen K, Rogala KB, Chou H-T, et al. Cryo-EM structure of the human FLCN-FNIP2-rag-ragulator complex. Cell. 2019;179(6):1319–1329.e8.
  • Lawrence RE, Fromm SA, Fu Y, et al. Structural mechanism of a rag GTPase activation checkpoint by the lysosomal folliculin complex. Science. 2019;366(6468):971–977. DOI:10.1126/science.aax0364.
  • Dunlop EA, Seifan S, Claessens T, et al. FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy. 2014;10(10):1749–1760. DOI:10.4161/auto.29640.
  • Zhong M, Zhao X, Li J, et al. Tumor suppressor folliculin regulates mTORC1 through primary cilia. J Biol Chem. 2016;291(22):11689–11697. DOI:10.1074/jbc.M116.719997.
  • Barron JC, Hurley EP, Parsons MP. Huntingtin and the synapse. Front Cell Neurosci. 2021;15:689332.
  • Rui YN, Xu Z, Patel B, et al. Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol. 2015;17(3):262–275. DOI:10.1038/ncb3101.
  • Kaliszewski M, Knott AB, Bossy-Wetzel E. Primary cilia and autophagic dysfunction in Huntington’s disease. Cell Death Differ. 2015;22(9):9–24.
  • Yehia L, Keel E, Eng C. The clinical spectrum of PTEN mutations. Annu Rev Med. 2020;71(1):103–116.
  • Arico S, Petiot A, Bauvy C, et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem. 2001;276(38):805–808. DOI:10.1074/jbc.C100319200.
  • Niu Y, Sun W, Lu -J-J, et al. PTEN activation by DNA damage induces protective autophagy in response to cucurbitacin B in hepatocellular carcinoma cells. Oxid Med Cell Longev. 2016;2016:1–15.
  • Shnitsar I, Bashkurov M, Masson GR, et al. PTEN regulates cilia through dishevelled. Nat Commun. 2015;6(1):8388.
  • Peixoto E, Jin S, Thelen K, et al. HDAC6-dependent ciliophagy is involved in ciliary loss and cholangiocarcinoma growth in human cells and murine models. Am J Physiol Liver Physiol. 2020;318(6):G1022–33.
  • Xu Q, Liu W, Liu X, et al. Type I collagen promotes primary cilia growth through down-regulating HDAC6-mediated autophagy in confluent mouse embryo fibroblast 3T3-L1 cells. J Biosci Bioeng. 2018;125(1):8–14. DOI:10.1016/j.jbiosc.2017.07.012.
  • Lee J, Yi S, Kang YE, et al. Defective ciliogenesis in thyroid hürthle cell tumors is associated with increased autophagy. Oncotarget. 2016;7(48):79117–79130. DOI:10.18632/oncotarget.12997.
  • Coene KLM, Roepman R, Doherty D, et al. OFD1 is mutated in X-linked joubert syndrome and interacts with LCA5-encoded lebercilin. Am J Hum Genet. 2009;85(4):465–481. DOI:10.1016/j.ajhg.2009.09.002.
  • Conciliis de L, Marchitiello A, Wapenaar MC, et al. Characterization of Cxorf5 (71-7A), a novel human cDNA mapping to Xp22 and encoding a protein containing coiled-coila-helical domains. Genomics. 1998;51(2):243–250. DOI:10.1006/geno.1998.5348.
  • Ferrante MI, Feather SA, Bulfone A, et al. Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet. 2001;68(3):569–576. DOI:10.1086/318802.
  • Bukowy-Bieryllo Z, Rabiasz A, Dabrowski M, et al. Truncating mutations in exons 20 and 21 of OFD1 can cause primary ciliary dyskinesia without associated syndromic symptoms. J Med Genet. 2019;56(11):769–777. DOI:10.1136/jmedgenet-2018-105918.
  • Hannah WB, DeBrosse S, Kinghorn B, et al. The expanding phenotype of OFD1 -related disorders: hemizygous loss-of-function variants in three patients with primary ciliary dyskinesia. Mol Genet Genomic Med. 2019;7(9):9. DOI:10.1002/mgg3.911.
  • Webb TR, Parfitt DA, Gardner JC, et al. Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23). Hum Mol Genet. 2012;21(16):3647–3654. DOI:10.1093/hmg/dds194.
  • Budny B, Chen W, Omran H, et al. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral–facial–digital type I syndrome. Hum Genet. 2006;120(2):243–250. DOI:10.1007/s00439-006-0210-5.
  • European polycystic kidney dise T. Consortium TEPD The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell. 1994;77(6):881–894.
  • Mochizuki T, Wu G, Hayashi T, et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science. 1996;272(5266):1339–1342. DOI:10.1126/science.272.5266.1339.
  • Foerster P, Daclin M, Asm S, et al. mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis. Development. 2017;144(2):201–210. DOI:10.1242/dev.138271.
  • Yuan S, Li J, Diener DR, et al. Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation. Proc Natl Acad Sci U S A. 2012;109(6):2021–2026. DOI:10.1073/pnas.1112834109.
  • Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960–976.
  • McMaster ML, Goldstein AM, Parry DM. Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population. J Med Genet. 2011;48(7):444–449.
  • Jacoby M, Cox JJ, Gayral S, et al. INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet. 2009;41(9):1027–1031. DOI:10.1038/ng.427.
  • Zhang X, Jefferson AB, Auethavekiat V, et al. The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase. Proc Natl Acad Sci U S A. 1995;92(11):4853–4856. DOI:10.1073/pnas.92.11.4853.
  • Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the birt-hogg-dube syndrome. Cancer Cell. 2002;2(2):157–164. DOI:10.1016/S1535-6108(02)00104-6.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.