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Active transport and diffusion barriers restrict Joubert Syndrome-associated ARL13B/ARL-13 to an Inv-like ciliary membrane subdomain.

التفاصيل البيبلوغرافية
العنوان: Active transport and diffusion barriers restrict Joubert Syndrome-associated ARL13B/ARL-13 to an Inv-like ciliary membrane subdomain.
المؤلفون: Sebiha Cevik, Anna A W M Sanders, Erwin Van Wijk, Karsten Boldt, Lara Clarke, Jeroen van Reeuwijk, Yuji Hori, Nicola Horn, Lisette Hetterschijt, Anita Wdowicz, Andrea Mullins, Katarzyna Kida, Oktay I Kaplan, Sylvia E C van Beersum, Ka Man Wu, Stef J F Letteboer, Dorus A Mans, Toshiaki Katada, Kenji Kontani, Marius Ueffing, Ronald Roepman, Hannie Kremer, Oliver E Blacque
المصدر: PLoS Genetics, Vol 9, Iss 12, p e1003977 (2013)
بيانات النشر: Public Library of Science (PLoS), 2013.
سنة النشر: 2013
المجموعة: LCC:Genetics
مصطلحات موضوعية: Genetics, QH426-470
الوصف: Cilia are microtubule-based cell appendages, serving motility, chemo-/mechano-/photo- sensation, and developmental signaling functions. Cilia are comprised of distinct structural and functional subregions including the basal body, transition zone (TZ) and inversin (Inv) compartments, and defects in this organelle are associated with an expanding spectrum of inherited disorders including Bardet-Biedl syndrome (BBS), Meckel-Gruber Syndrome (MKS), Joubert Syndrome (JS) and Nephronophthisis (NPHP). Despite major advances in understanding ciliary trafficking pathways such as intraflagellar transport (IFT), how proteins are transported to subciliary membranes remains poorly understood. Using Caenorhabditis elegans and mammalian cells, we investigated the transport mechanisms underlying compartmentalization of JS-associated ARL13B/ARL-13, which we previously found is restricted at proximal ciliary membranes. We now show evolutionary conservation of ARL13B/ARL-13 localisation to an Inv-like subciliary membrane compartment, excluding the TZ, in many C. elegans ciliated neurons and in a subset of mammalian ciliary subtypes. Compartmentalisation of C. elegans ARL-13 requires a C-terminal RVVP motif and membrane anchoring to prevent distal cilium and nuclear targeting, respectively. Quantitative imaging in more than 20 mutants revealed differential contributions for IFT and ciliopathy modules in defining the ARL-13 compartment; IFT-A/B, IFT-dynein and BBS genes prevent ARL-13 accumulation at periciliary membranes, whereas MKS/NPHP modules additionally inhibit ARL-13 association with TZ membranes. Furthermore, in vivo FRAP analyses revealed distinct roles for IFT and MKS/NPHP genes in regulating a TZ barrier to ARL-13 diffusion, and intraciliary ARL-13 diffusion. Finally, C. elegans ARL-13 undergoes IFT-like motility and quantitative protein complex analysis of human ARL13B identified functional associations with IFT-B complexes, mapped to IFT46 and IFT74 interactions. Together, these findings reveal distinct requirements for sequence motifs, IFT and ciliopathy modules in defining an ARL-13 subciliary membrane compartment. We conclude that MKS/NPHP modules comprise a TZ barrier to ARL-13 diffusion, whereas IFT genes predominantly facilitate ARL-13 ciliary entry and/or retention via active transport mechanisms.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1553-7390
1553-7404
Relation: http://europepmc.org/articles/PMC3854969?pdf=render; https://doaj.org/toc/1553-7390; https://doaj.org/toc/1553-7404
DOI: 10.1371/journal.pgen.1003977
URL الوصول: https://doaj.org/article/566785b284434b95974086b530bbc77f
رقم الأكسشن: edsdoj.566785b284434b95974086b530bbc77f
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:15537390
15537404
DOI:10.1371/journal.pgen.1003977