期刊
NATURE CELL BIOLOGY
卷 18, 期 1, 页码 122-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3273
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资金
- European Community's Seventh Framework Programme [241955]
- Science Foundation Ireland [11/PI/1037]
- Dutch Kidney Foundation [CP11.18]
- GIS-Institut des Maladies Rares
- French Fondation for Rare Disease
- Virgo consortium [FE50908]
- Netherlands Genomics Initiative [050-060-452]
- French Ministry of Health (PHRC national) [2010-A01014-35]
- Fondation pour la Recherche Medicale [DEQ20130326532]
- Regional Council of Burgundy
- Sir Jules Thorn Award for Biomedical Research [JTA/09]
- UK Medical Research Council [MR/K011154/1, MR1K015613/1]
- Lung GO Sequencing Project [HL-102923]
- WHI Sequencing Project [HL-102924]
- Broad GO Sequencing Project [HL-102925]
- Seattle GO Sequencing Project [HL-102926]
- Heart GO Sequencing Project [HL-103010]
- University of Leeds
- MRC [MR/K015613/1, MR/K011154/1, MR/M000532/1] Funding Source: UKRI
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [UC2HL102925, RC2HL102926, UC2HL102924, UC2HL102926, RC2HL102925, UC2HL103010, RC2HL103010, RC2HL102923, RC2HL102924, UC2HL102923] Funding Source: NIH RePORTER
- Medical Research Council [MR/K011154/1, MR/M000532/1, MR/K015613/1] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [09JTA] Funding Source: researchfish
The transition zone (TZ) ciliary subcompartment is thought to control cilium composition and signalling by facilitating a protein diffusion barrier at the ciliary base. TZ defects cause ciliopathies such as Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP) and Joubert syndrome' (JBTS). However, the molecular composition and mechanisms underpinning TZ organization and barrier regulation are poorly understood. To uncover candidate TZ genes, we employed bioinformatics (coexpression and co-evolution) and identified TMEM107 as a TZ protein mutated in oral-facial-digital syndrome and JBTS patients. Mechanistic studies in Caenorhabditis elegans showed that TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors. Furthermore, nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237). Finally, MKS module membrane proteins are immobile and super-resolution microscopy in worms and mammalian cells reveals periodic localizations within the TZ. This work expands the MKS module of ciliopathy-causing TZ proteins associated with diffusion barrier formation and provides insight into TZ subdomain architecture.
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