General and cell-type specific mechanisms target TRPP2/PKD-2 to cilia

Bae, Young Kyung; Qin, Hongmin; Knobel, Karla M.; Hu, Jinghua; Rosenbaum, Joel L.; Barr, Maureen M.

doi:10.1242/dev.02555

Cited by 99 publications

(146 citation statements)

References 81 publications

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“…A conclusion both from this work, as well as from previous studies, is that C. elegans sensory neurons do not appear to contain a mechanism that acts generally and broadly to sort all cilia-destined membrane proteins (e.g., Bae et al 2006;Wojtyniak et al 2013). For instance, although the DAF-25 Ankmy2 protein regulates ciliary localization of all GPCRs examined in this work, previous studies have shown that mutations in daf-25 affect localization of only a subset of other ciliary membrane proteins, including GPCRs, in different cell types (Fujiwara et al 2010;Wojtyniak et al 2013).…”

Section: Discussionmentioning

confidence: 49%

“…The clathrin adaptor AP-1 complex has been suggested to act broadly to retrieve cilia-targeted membrane proteins from a default trafficking pathway that would otherwise sort these proteins to the general cellular membrane compartment . Indeed, in AP-1 complex mutants, multiple ciliary membrane proteins including channels and GPCRs are mistargeted to the nonciliary plasma membrane Bae et al 2006;Kaplan et al 2010). However, our results indicate that the AP-1 complex acts in a protein-and cell-specific manner to target GPCRs to cilia such that localization of STR-44, but not STR-163, to AWB cilia is affected in unc-101 mutants, whereas UNC-101 is required for ciliary localization of both STR-163 and SRBC-64 in ASK.…”

Section: Discussionmentioning

confidence: 99%

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

Brear

Yoon

Wojtyniak³

et al. 2014

Genetics

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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...

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

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

Brear

Yoon

Wojtyniak³

et al. 2014

Genetics

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“…We found that the localization of these proteins was essentially undisturbed in ciliary tubulin mutants, consistent with the idea that TBA-6, TBA-9, and TBB-4 are more important for specialized cilium functions than for general aspects of ciliogenesis. In contrast, previous work in C. elegans has shown that cell type-specific factors, including the kinesinlike protein KLP-6, are important for the proper transport of signaling molecules in particular types of ciliated neurons (Peden and Barr 2005;Bae et al 2006;Jauregui et al 2008;Bae et al 2009). Here, we find that some specialized cilia, especially those of the CEM neurons, are particularly dependent on tba-6 and tbb-4 function.…”

Section: Discussionmentioning

confidence: 79%

Specific α- and β-Tubulin Isotypes Optimize the Functions of Sensory Cilia inCaenorhabditis elegans

Hurd

Miller²,

Núñez

et al. 2010

Genetics

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Primary cilia have essential roles in transducing signals in eukaryotes. At their core is the ciliary axoneme, a microtubule-based structure that defines cilium morphology and provides a substrate for intraflagellar transport. However, the extent to which axonemal microtubules are specialized for sensory cilium function is unknown. In the nematode Caenorhabditis elegans, primary cilia are present at the dendritic ends of most sensory neurons, where they provide a specialized environment for the transduction of particular stimuli. Here, we find that three tubulin isotypes-the a-tubulins TBA-6 and TBA-9 and the b-tubulin TBB-4-are specifically expressed in overlapping sets of C. elegans sensory neurons and localize to the sensory cilia of these cells. Although cilia still form in mutants lacking tba-6, tba-9, and tbb-4, ciliary function is often compromised: these mutants exhibit a variety of sensory deficits as well as the mislocalization of signaling components. In at least one case, that of the CEM cephalic sensory neurons, cilium architecture is disrupted in mutants lacking specific ciliary tubulins. While there is likely to be some functional redundancy among C. elegans tubulin genes, our results indicate that specific tubulins optimize the functional properties of C. elegans sensory cilia.

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“…14 Transport of polycystins to the primary cilium is tightly regulated and several mediators of different trafficking steps have been identified to direct vesicles to the primary cilium base. 3,[15][16][17] In this region, known as basal body, a selective barrier regulates entry of specific proteins inside the ciliary compartment. 18,19 A key player in this selective entry of ciliary components is the small guanosine triphosphatase (GTPase) Rab8.…”

mentioning

confidence: 99%

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

Franco

Margaria

Santis

et al. 2016

Journal of the American Society of Nephrology

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Signaling from the primary cilium regulates kidney tubule development and cyst formation. However, the mechanism controlling targeting of ciliary components necessary for cilium morphogenesis and signaling is largely unknown. Here, we studied the function of class II phosphoinositide 3-kinase-C2a (PI3K-C2a) in renal tubule-derived inner medullary collecting duct 3 cells and show that PI3K-C2a resides at the recycling endosome compartment in proximity to the primary cilium base. In this subcellular location, PI3K-C2a controlled the activation of Rab8, a key mediator of cargo protein targeting to the primary cilium. Consistently, partial reduction of PI3K-C2a was sufficient to impair elongation of the cilium and the ciliary transport of polycystin-2, as well as to alter proliferation signals linked to polycystin activity. In agreement, heterozygous deletion of PI3K-C2a in mice induced cilium elongation defects in kidney tubules and predisposed animals to cyst development, either in genetic models of polycystin-1/2 reduction or in response to ischemia/reperfusion-induced renal damage. These results indicate that PI3K-C2a is required for the transport of ciliary components such as polycystin-2, and partial loss of this enzyme is sufficient to exacerbate the pathogenesis of cystic kidney disease.

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General and cell-type specific mechanisms target TRPP2/PKD-2 to cilia

Cited by 99 publications

References 81 publications

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

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

Specific α- and β-Tubulin Isotypes Optimize the Functions of Sensory Cilia inCaenorhabditis elegans

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

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