A Novel Protein LZTFL1 Regulates Ciliary Trafficking of the BBSome and Smoothened

English version České info

Many signaling proteins including G protein-coupled receptors localize to primary cilia, regulating cellular processes including differentiation, proliferation, organogenesis, and tumorigenesis. Bardet-Biedl Syndrome (BBS) proteins are involved in maintaining ciliary function by mediating protein trafficking to the cilia. However, the mechanisms governing ciliary trafficking by BBS proteins are not well understood. Here, we show that a novel protein, Leucine-zipper transcription factor-like 1 (LZTFL1), interacts with a BBS protein complex known as the BBSome and regulates ciliary trafficking of this complex. We also show that all BBSome subunits and BBS3 (also known as ARL6) are required for BBSome ciliary entry and that reduction of LZTFL1 restores BBSome trafficking to cilia in BBS3 and BBS5 depleted cells. Finally, we found that BBS proteins and LZTFL1 regulate ciliary trafficking of hedgehog signal transducer, Smoothened. Our findings suggest that LZTFL1 is an important regulator of BBSome ciliary trafficking and hedgehog signaling.

Vyšlo v časopise: A Novel Protein LZTFL1 Regulates Ciliary Trafficking of the BBSome and Smoothened. PLoS Genet 7(11): e32767. doi:10.1371/journal.pgen.1002358
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002358

Souhrn

Zdroje

1. SinglaVReiterJF 2006 The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 313 629 633

2. GoetzSCAndersonKV 2010 The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11 331 344

3. QuinlanRJTobinJLBealesPL 2008 Modeling ciliopathies: Primary cilia in development and disease. Curr Top Dev Biol 84 249 310

4. BadanoJLMitsumaNBealesPLKatsanisN 2006 The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7 125 148

5. ZaghloulNAKatsanisN 2009 Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest 119 428 437

6. KimSKShindoAParkTJOhECGhoshS 2010 Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science 329 1337 1340

7. OttoEAHurdTWAirikRChakiMZhouW 2010 Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet 42 840 850

8. SeoSBayeLMSchulzNPBeckJSZhangQ 2010 BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc Natl Acad Sci U S A 107 1488 1493

9. NachuryMVLoktevAVZhangQWestlakeCJPeranenJ 2007 A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129 1201 1213

10. LoktevAVZhangQBeckJSSearbyCCScheetzTE 2008 A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell 15 854 865

11. JinHWhiteSRShidaTSchulzSAguiarM 2010 The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141 1208 1219

12. DomireJSGreenJALeeKGJohnsonADAskwithCC 2010 Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins. Cell Mol Life Sci DOI:10.1007/s00018-00010-00603-00014

13. BerbariNFLewisJSBishopGAAskwithCCMykytynK 2008 Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A 105 4242 4246

14. LechtreckKFJohnsonECSakaiTCochranDBallifBA 2009 The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J Cell Biol 187 1117 1132

15. CorbitKCAanstadPSinglaVNormanARStainierDY 2005 Vertebrate Smoothened functions at the primary cilium. Nature 437 1018 1021

16. KissHKedraDKissCKost-AlimovaMYangY 2001 The LZTFL1 gene is a part of a transcriptional map covering 250 kb within the common eliminated region 1 (C3CER1) in 3p21.3. Genomics 73 10 19

17. WeiQZhouWWangWGaoBWangL 2010 Tumor-suppressive functions of leucine zipper transcription factor-like 1. Cancer Res 70 2942 2950

18. SuttonRBFasshauerDJahnRBrungerAT 1998 Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature 395 347 353

19. MisuraKMSchellerRHWeisWI 2001 Self-association of the H3 region of syntaxin 1A. Implications for intermediates in SNARE complex assembly. J Biol Chem 276 13273 13282

20. SoderbergOGullbergMJarviusMRidderstraleKLeuchowiusKJ 2006 Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods 3 995 1000

21. OuGKogaMBlacqueOEMurayamaTOhshimaY 2007 Sensory ciliogenesis in Caenorhabditis elegans: assignment of IFT components into distinct modules based on transport and phenotypic profiles. Mol Biol Cell 18 1554 1569

22. OcbinaPJAndersonKV 2008 Intraflagellar transport, cilia, and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev Dyn 237 2030 2038

23. KimJKatoMBeachyPA 2009 Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus. Proc Natl Acad Sci U S A 106 21666 21671

24. RohatgiRMilenkovicLCorcoranRBScottMP 2009 Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci U S A 106 3196 3201

25. NishimuraDYFathMMullinsRFSearbyCAndrewsM 2004 Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proc Natl Acad Sci U S A 101 16588 16593

26. MykytynKMullinsRFAndrewsMChiangAPSwiderskiRE 2004 Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proc Natl Acad Sci U S A 101 8664 8669.0

27. KishimotoNCaoYParkASunZ 2008 Cystic kidney gene seahorse regulates cilia-mediated processes and Wnt pathways. Developmental cell 14 954 961

28. KimJCBadanoJLSiboldSEsmailMAHillJ 2004 The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 36 462 470

29. HaycraftCJZhangQSongBJacksonWSDetloffPJ 2007 Intraflagellar transport is essential for endochondral bone formation. Development 134 307 316

30. TranPVHaycraftCJBesschetnovaTYTurbe-DoanAStottmannRW 2008 THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet 40 403 410

31. TobinJLDi FrancoMEichersEMay-SimeraHGarciaM 2008 Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet-Biedl syndrome. Proc Natl Acad Sci U S A 105 6714 6719

32. Garcia-GonzaloFRCorbitKCSirerol-PiquerMSRamaswamiGOttoEA 2011 A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nature genetics 43 776 784

33. SangLMillerJJCorbitKCGilesRHBrauerMJ 2011 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145 513 528

34. WilliamsCLLiCKidaKInglisPNMohanS 2011 MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. The Journal of cell biology 192 1023 1041

35. CraigeBTsaoCCDienerDRHouYLechtreckKF 2010 CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content. J Cell Biol 190 927 940

36. LivakKJSchmittgenTD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25 402 408

37. ArnoldKBordoliLKoppJSchwedeT 2006 The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22 195 201

38. ZdobnovEMApweilerR 2001 InterProScan–an integration platform for the signature-recognition methods in InterPro. Bioinformatics 17 847 848