Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins

Badgandi, Hemant B.; Hwang, Sun Hee; Shimada, Issei S.; Loriot, Evan; Mukhopadhyay, Sutapa

doi:10.1083/jcb.201607095

Cited by 153 publications

(249 citation statements)

References 87 publications

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“…Further, Sstr3 is likely to be one of the many GPCRs contributing to IN development. The expression and function of other cilia localized GPCRs (e.g., D1R, D2R, D5R, NPY2R, NPY5R, PGR15L, Gpr161, GPR19/83/88, GAL2R, GAL3R, HTR6, KISS1R, MCHR1, NPFFR1, P2RY1, PRHLR, and QRFPR) in INs remains to be characterized (Badgandi et al, 2017; Loktev and Jackoson, 2013). The lack of rescue with D124E-Sstr3 confirms the importance of cilary Sstr3 activity in INs, but other non- ciliary roles of Sstr3 in these neurons cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity

et al. 2017

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Summary Appropriate growth and synaptic integration of GABAergic inhibitory interneurons are essential for functional neural circuits in the brain. Here, we demonstrate that disruption of primary cilia function following the selective loss of ciliary GTPase Arl13b in interneurons impairs interneuronal morphology and synaptic connectivity, leading to altered excitatory/inhibitory activity (E/I) balance. The altered morphology and connectivity of cilia mutant interneurons and the functional deficits are rescued by either chemogenetic activation of ciliary GPCR signaling or the selective induction of Sstr3, a ciliary-GPCR, in Arl13b deficient cilia. Our results thus define a specific requirement for primary cilia-mediated GPCR signaling in interneuronal connectivity and inhibitory circuit formation.

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Section: Discussionmentioning

confidence: 99%

Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity

et al. 2017

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“…Gpr161 determines PKA-mediated Gli3R formation by constitutive cAMP signaling (Mukhopadhyay et al, 2013). Furthermore, the intraflagellar transport A (IFT-A) core complex and the tubby family protein Tulp3 coordinate Gpr161 trafficking to cilia (Badgandi et al, 2017), with either IFT-A or Tulp3 mutants exhibiting high Shh signaling, unlike other mutants affecting cilia (Goetz and Anderson, 2010). Here we describe the role of Gpr161 in development of Shh-MBs by restricting premature and postnatal Shh signaling, ultimately limiting GC progenitor generation and proliferation.…”

Section: Introductionmentioning

confidence: 99%

Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis

et al. 2018

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SUMMARY Sonic hedgehog (Shh) determines cerebellar granule cell (GC) progenitor proliferation and medulloblastoma pathogenesis. However, the pathways regulating GC progenitors during embryogenesis before Shh production by Purkinje neurons and their roles in tumorigenesis remain unclear. The cilium-localized G-protein-coupled receptor Gpr161 suppresses Shh-mediated signaling in the neural tube. Here, by deleting Gpr161 in mouse neural stem cells or GC progenitors, we establish Gpr161 as a tumor suppressor in Shh subtype medulloblastoma. Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors. Moreover, earlier deletion of Gpr161 during embryogenesis increased tumor incidence and severity. GC progenitor overproduction during embryogenesis from Gpr161 deletion was cilium dependent, unlike normal development. Low GPR161 expression correlated with poor survival of SHH subtype medulloblastoma patients. Gpr161 restricts GC progenitor production by preventing premature and Shh-dependent pathway activity, highlighting the importance of basal pathway suppression in tumorigenesis.

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“…The ciliary localization of TULP3, a Tubby-family protein that binds PI(4,5)P 2 [131], increases as ciliary PI(4,5)P 2 increases and PI(4)P decreases, suggesting that ciliary TULP3 levels are restrained by wild type ciliary phosphoinositide composition [43,44]. In a PI(4,5)P 2 -dependent fashion, TULP3 binds to the IFT-A complex and helps deliver diverse membrane-associated proteins to cilia, including GPCRs and PKD2 [131–133]. However, when TULP3 encounters PI(4)P in cilia, it may disassociate from the membrane and release its cargo within the ciliary membrane [44,133].…”

Section: Phosphoinositide Compartmentalization and Consequences Of Abmentioning

confidence: 99%

“…In a PI(4,5)P 2 -dependent fashion, TULP3 binds to the IFT-A complex and helps deliver diverse membrane-associated proteins to cilia, including GPCRs and PKD2 [131–133]. However, when TULP3 encounters PI(4)P in cilia, it may disassociate from the membrane and release its cargo within the ciliary membrane [44,133]. Loss of function mutations affecting TULP3, components of the IFT-A complex, or the ciliary GPCR GPR161 cause misactivation of Hedgehog signaling [132,134–139].…”

Section: Phosphoinositide Compartmentalization and Consequences Of Abmentioning

confidence: 99%

“…In support of this possibility, mutation of either the founding member of the family, TUBBY, or its paralog, TULP1, are associated with obesity and retinal degeneration, phenotypes also observed in ciliopathies [140–142]. TUBBY is expressed predominantly by the retina and brain, and, like TULP3, it is involved in localizing GPCRs to cilia [133,143]. It is possible that photoreceptor phosphoinositides are read out by TUBBY and TULP1 to promote the delivery of Rhodopsin to the outer segment, defects in which cause photoreceptor loss, and read out by TUBBY to promote the delivery of MC4R to the paraventricular nucleus cilium [144], defects in which cause obesity.…”

Section: Phosphoinositide Compartmentalization and Consequences Of Abmentioning

confidence: 99%

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How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In

2018

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Cilia, organelles that move to execute functions like fertilization and signal to execute functions like photoreception and embryonic patterning, are composed of a core of nine-fold doublet microtubules overlain by a membrane. Distinct types of cilia display distinct membrane morphologies, ranging from simple domed cylinders to the highly ornate invaginations and membrane disks of photoreceptor outer segments. Critical for the ability of cilia to signal, both the protein and the lipid compositions of ciliary membranes are different from those of other cellular membranes. This specialization presents a unique challenge for the cell as, unlike membrane-bounded organelles, the ciliary membrane is contiguous with the surrounding plasma membrane. This distinct ciliary membrane is generated in concert with multiple membrane remodeling events that comprise the process of ciliogenesis. Once the cilium is formed, control of ciliary membrane composition relies on discrete molecular machines, including a barrier to membrane proteins entering the cilium at a specialized region of the base of the cilium called the transition zone and a trafficking adaptor that controls G protein-coupled receptor (GPCR) localization to the cilium called the BBSome. The ciliary membrane can be further remodeled by the removal of membrane proteins by the release of ciliary extracellular vesicles that may function in intercellular communication, removal of unneeded proteins or ciliary disassembly. Here, we review the structures and transport mechanisms that control ciliary membrane composition, and discuss how membrane specialization enables the cilium to function as the antenna of the cell.

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Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins

Abstract: Trafficking of integral membrane proteins to cilia is poorly understood. Badgandi et al. show that tubby family proteins TULP3 and TUB act as general adapters for ciliary trafficking of structurally diverse integral membrane cargo like GCPRs and the polycystin 1/2 complex.

Cited by 153 publications

References 87 publications

Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity

Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity

Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis

How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In

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