A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain

Chih, Ben; Liu, Peter; Chinn, Y. Eugene; Chalouni, Cécile; Kömüves, László G.; Hass, Philip E.; Sandoval, Wendy; Peterson, Andrew S.

doi:10.1038/ncb2410

Cited by 320 publications

(444 citation statements)

References 42 publications

Supporting

Mentioning

419

Contrasting

Order By: Relevance

“…B9D1 and CC2D2A colocalize at the transition zone of the cilium and belong to a conglomerate of proteins called the B9 complex. [31][32][33][34] Several other JBS proteins are also predicted to be part of this complex. These simultaneous variants in CC2D2A and B9D1 may suggest a digenic or triallelic inheritance model given the functional interaction between the two proteins.…”

Section: Non-mendelian Inheritance and B9d1mentioning

confidence: 99%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

View full text Add to dashboard Cite

Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with 420 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel-Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding.

show abstract

Section: Non-mendelian Inheritance and B9d1mentioning

confidence: 99%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Morphological structures that could potentially play such a barrier role include the FP collar and collarette that have been identified by electron tomography in T. brucei (46). In both mammalian cells and Caenorhabditis elegans, multisubunit complexes such as Tectonic complex (47), B9 complex (48), and the MKS/MKSR/ NPHP complex (49) form a ciliary gate that prevents diffusion of non-ciliary proteins into the ciliary membrane. In contrast, the mammalian protein Septin 2, a membrane-associated GTPase, is required for formation of a ciliary diffusion barrier that retains ciliary membrane proteins within the cilium (50).…”

Section: Kh1 Is Critical For Viability Of Intracellularmentioning

confidence: 99%

KHARON1 Mediates Flagellar Targeting of a Glucose Transporter in Leishmania mexicana and Is Critical for Viability of Infectious Intracellular Amastigotes

Tran

Rodriguez‐Contreras

Vieira

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The mechanism for selectively targeting membrane proteins to the flagellum of kinetoplastid parasites is unknown. Results: We have identified a novel protein, KHARON1, which is important for the flagellar targeting of a glucose transporter. Conclusion: KHARON1 is the first protein identified in Kinetoplastida that targets a membrane protein to the flagellum. Significance: KHARON1 may be part of a new flagellar targeting pathway.

show abstract

“…This gate is composed of a large multiprotein complex including MKS and NPHP protein modules, which interact genetically and physically, although the exact interactions may be organism and/or cell type-specific Hu et al 2010;Sang et al 2011;Chih et al 2012). Mutations in one or more of these proteins can result in defects in ciliary membrane protein composition (McEwen et al 2007;Craige et al 2010;Chih et al 2012;Lechtreck et al 2013). We found that loss of multiple components of the MKS module in mks-1; mksr-2; mksr-1 triple mutants did not affect GPCR localization in either AWB or ASK (Table 4).…”

Section: Transition Zone Proteinsmentioning

confidence: 99%

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia

Brear

Yoon

Wojtyniak³

et al. 2014

Genetics

View full text Add to dashboard Cite

The localization of signaling molecules such as G protein-coupled receptors (GPCRs) to primary cilia is essential for correct signal transduction. Detailed studies over the past decade have begun to elucidate the diverse sequences and trafficking mechanisms that sort and transport GPCRs to the ciliary compartment. However, a systematic analysis of the pathways required for ciliary targeting of multiple GPCRs in different cell types in vivo has not been reported. Here we describe the sequences and proteins required to localize GPCRs to the cilia of the AWB and ASK sensory neuron types in Caenorhabditis elegans. We find that GPCRs expressed in AWB or ASK utilize conserved and novel sequences for ciliary localization, and that the requirement for a ciliary targeting sequence in a given GPCR is different in different neuron types. Consistent with the presence of multiple ciliary targeting sequences, we identify diverse proteins required for ciliary localization of individual GPCRs in AWB and ASK. In particular, we show that the TUB-1 Tubby protein is required for ciliary localization of a subset of GPCRs, implying that defects in GPCR localization may be causal to the metabolic phenotypes of tub-1 mutants. Together, our results describe a remarkable complexity of mechanisms that act in a protein-and cellspecific manner to localize GPCRs to cilia, and suggest that this diversity allows for precise regulation of GPCR-mediated signaling as a function of external and internal context. SIGNALING molecules must be precisely localized to specific subcellular domains to optimize detection and transduction of external stimuli. G protein-coupled receptors (GPCRs) comprise a large family of transmembrane signaling proteins that directly bind and transduce a range of cues including photons, odorants, neurotransmitters, and peptides (Pierce et al. 2002;Kato and Touhara 2009;Demaria and Ngai 2010;Sung and Chuang 2010;Chamero et al. 2012;Frooninckx et al. 2012;Montell 2012;Bathgate et al. 2013). Regulation of GPCR function, including regulation of membrane targeting and trafficking to specific subcellular regions, is a major contributor to the tuning of signaling efficacy and fidelity (e.g., Deretic et al. 1995;Ango et al. 2000;Xia et al. 2003;Esseltine et al. 2012;. However, much remains to be understood regarding the mechanisms by which GPCR trafficking and membrane localization are regulated.GPCR-mediated signal transduction in many cellular contexts requires these proteins to be localized to specialized microtubule-based primary cilia. For example, in photoreceptors and olfactory neurons, efficient sensory signal transduction is mediated via localization of rhodopsin and olfactory receptors, together with other signaling molecules, to photoreceptor outer segments and olfactory neuron cilia, respectively (Insinna and Besharse 2008;Berbari et al. 2009;Pifferi et al. 2010;Deretic and Wang 2012). Receptors in the Hedgehog (Hh) morphogen signaling pathway such as the Smoothened and Patched transmembrane proteins, and the G...

show abstract

A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain

Cited by 320 publications

References 42 publications

Joubert syndrome: genotyping a Northern European patient cohort

Joubert syndrome: genotyping a Northern European patient cohort

KHARON1 Mediates Flagellar Targeting of a Glucose Transporter in Leishmania mexicana and Is Critical for Viability of Infectious Intracellular Amastigotes

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia

Contact Info

Product

Resources

About