BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone

Ye, Fan; Nager, Andrew R.; Nachury, Maxence V.

doi:10.1083/jcb.201709041

Cited by 230 publications

(274 citation statements)

References 83 publications

(144 reference statements)

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“…This difference could have led to differences in responsiveness to pharmacological manipulation at the time of drug treatment on DIV9. Finally, intense overexpression of cilia-targeted receptors may alter the biology of cilia in unpredictable manners, especially since trafficking of GPCRs in and out of the primary cilium involves a complex interaction between intraflagellar transport complexes, "BBsome" proteins that are involved in complex network of interacting proteins that continues to be elucidated (Schou et al, 2015;Ye et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

et al. 2018

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receptors increases the likelihood for receptors to localize outside of the primary cilium and have been associated with changes in cilia morphology and dendritic outgrowth. In the present study, we explore the role of 5-HT6R rescue on neuronal morphology in primary neuronal cultures from 5-HT6R-KO mice, while maintaining a more physiological level of expression, wherein the receptor localizes to cilia in 80-90% of neurons (similar to endogenous 5-HT6R localization). We found that rescue of 5-HT6R expression is sufficient to increase cilia length and dendritic outgrowth, but primarily in neurons in which the receptor is located exclusively in the primary cilia. Additionally, we found that expression of 5-HT6R mutants, deficient in agonist-stimulated cAMP or without the predicted Fyn kinase binding domain, maintain constitutive activity for stimulating cAMP and still increased the length of cilia, while the proposed Fyn kinase domain was required for stimulating dendritic outgrowth. These findings highlight the complexity of 5-HT6R function and localization, particularly when using exogenous overexpression, and provide greater understanding and potential mechanisms for 5-HT6R drug therapies.

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Section: Discussionmentioning

confidence: 99%

Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

et al. 2018

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“…Accumulation of STX3 and STXBP1 in the outer segment is a phenotype commonly observed in BBS mutant photoreceptors [45][46][47]. While CEP290 is a stationary protein constituting the ciliary gate, BBSomes (a protein complex composed of 8 BBS proteins [56,57]) are adapter complexes that link ciliary cargos to IFT particles and transport them in and out of the ciliary compartment [58][59][60][61][62][63][64][65]. To test whether STX3 and STXBP1 mislocalization in Cep290 fl/fl ;Cre + retinas is mediated by loss or dysfunction of the BBSome, we examined the quantity and localization of BBSome components as well as a BBSome regulator LZTFL1 [66].…”

Section: Mislocalization Of Inner Segment Membrane Proteins In Cep290mentioning

confidence: 99%

CEP290 myosin-tail homology domain is essential for protein confinement between inner and outer segments in photoreceptors

Datta

Hendrickson

Brendalen

et al. 2019

Preprint

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Mutations in CEP290 cause various ciliopathies involving retinal degeneration. CEP290 proteins localize to the ciliary transition zone and are thought to act as a gatekeeper that controls ciliary protein trafficking. However, precise roles of CEP290 in photoreceptors and pathomechanisms of retinal degeneration in CEP290-associated ciliopathies are not sufficiently understood. Using Cep290 conditional mutant mice, in which the C-terminal myosin-tail homology domain is disrupted after the connecting cilium is assembled, we show that CEP290, more specifically the myosin-tail homology domain of CEP290, is essential for protein confinement between the inner and the outer segments.Inner segment plasma membrane proteins including STX3, SNAP25, and IMPG2 rapidly accumulate in the outer segment upon disruption of the myosin-tail homology domain. In contrast, localization of endomembrane proteins is not altered. Trafficking and confinement of most outer segment-resident proteins appear to be unaffected or only minimally affected in this mouse model. One notable exception is RHO, which exhibits severe mislocalization to inner segments from the initial stage of degeneration.Similar mislocalization phenotypes were observed in rd16 mice. These results suggest that failure of protein confinement at the connecting cilium and consequent accumulation of inner segment membrane proteins in the outer segment combined with insufficient RHO delivery is part of the disease mechanisms that cause retinal degeneration in CEP290-associated ciliopathies. Our study provides insights into the pathomechanisms of retinal degenerations associated with compromised ciliary gates.the absence of CEP290 in these organisms, ciliary protein compositions are altered [4,6]. In mammalian primary cilia, CEP290 is localized to the transition zone [7][8][9], and loss of CEP290 reduces ARL13B and ADCY3 levels within cilia while increasing the rate of ciliary entry of SMO in fibroblasts [10]. These studies establish the current model for CEP290 function: a ciliary gatekeeper that regulates protein trafficking in and out of the ciliary compartment at the transition zone [4][5][6][7][10][11][12][13]. In photoreceptors, CEP290 is localized to the connecting cilium [14,15] and expected to control protein movement between the inner and the outer segments.Mutations in human CEP290 cause various ciliopathies ranging from isolated retinal dystrophy (e.g.Leber congenital amaurosis (LCA)) to syndromic diseases such as neonatal lethal Meckel-Gruber Syndrome (MKS) with multi-organ malformations [16][17][18][19][20][21][22]. Despite considerable variations in phenotypic severity, retinopathy is present in almost all cases regardless of the involvement of other organs. This suggests that photoreceptors are particularly susceptible to deficiencies in CEP290 function. Based on the ciliary gatekeeper model, anticipated functions of CEP290 in photoreceptors include i) permitting or facilitating entry of outer segment-bound proteins into the outer segment, ii) blocking unauthoriz...

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“…The BBSome was initially shown to interact with RABIN8 to mediate ciliary membrane biogenesis [45] and ciliary localization of SSTR3 and MCHR1 [259], through the coating and sorting of ciliary-targeted vesicles [260]. Recent evidence indicates, however, that the BBSome primarily functions as a cargo adaptor for the retrograde IFT machinery to promote ciliary export of specific signalling receptors and other membrane proteins [258,[261][262][263]. Examples of ciliary membrane proteins that require the BBSome for ciliary export include SMO and PTCH1 in vertebrates [100,101,264], as well as PKD-2, OSM-9 and ODR-10 in C. elegans [265], and phospholipase D in Chlamydomonas [261].…”

Section: Role Of Ift-a Tubby Family Proteins and The Bbsome In Ciliamentioning

confidence: 99%

Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins

2018

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Primary cilia are antenna-like sensory organelles that regulate a substantial number of cellular signalling pathways in vertebrates, both during embryonic development as well as in adulthood, and mutations in genes coding for ciliary proteins are causative of an expanding group of pleiotropic diseases known as ciliopathies. Cilia consist of a microtubule-based axoneme core, which is subtended by a basal body and covered by a bilayer lipid membrane of unique protein and lipid composition. Cilia are dynamic organelles, and the ability of cells to regulate ciliary protein and lipid content in response to specific cellular and environmental cues is crucial for balancing ciliary signalling output. Here we discuss mechanisms involved in regulation of ciliary membrane protein trafficking and signalling, with main focus on kinesin-2 and kinesin-3 family members.

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BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone

Cited by 230 publications

References 83 publications

Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

CEP290 myosin-tail homology domain is essential for protein confinement between inner and outer segments in photoreceptors

Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins

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BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone

Cited by 230 publications

References 83 publications

Restoration of Physiological Expression of 5-HT6 Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

Restoration of Physiological Expression of 5-HT6 Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

CEP290 myosin-tail homology domain is essential for protein confinement between inner and outer segments in photoreceptors

Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins

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Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites