Requirement of IFT-B–BBSome complex interaction in export of GPR161 from cilia

Nozaki, Shohei; Araya, Roiner Francisco Castro; Katoh, Yohei; Nakayama, Kazuhisa

doi:10.1242/bio.043786

Cited by 41 publications

(42 citation statements)

References 59 publications

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“…Assuming the flat surface of the BBSome abuts the membrane, the opposite face would be free 28 to interact with the IFT complexes (IFT-A and IFT-B), with which they comigrate (Lechtreck et 29 al., 2009;Liew et al, 2014;Ou et al, 2005;Williams et al, 2014). Recent data from visible 30 immunoprecipitation experiments has mapped the interaction to BBS1, BBS2 and BBS9 of the 31 BBSome, and IFT38 of the IFT-B complex (Nozaki et al, 2019). This is consistent with the 1 copurification of BBSome subunits with endogeneously tagged IFT38 in a human cell line 2 (Beyer et al, 2018).…”

supporting

confidence: 52%

Structure and activation mechanism of the BBSome membrane-protein trafficking complex

Singh

Gui

Koh

et al. 2019

Preprint

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Bardet-Biedl syndrome (BBS) is an incurable ciliopathy caused by the failure to correctly 1 establish or maintain cilia-dependent signaling pathways. Eight proteins associated with BBS 2 assemble into the BBSome, a master regulator of the ciliary membrane proteome. We report the 3 electron cryomicroscopy (cryo-EM) structures of the native bovine BBSome in inactive and 4 active states at 3.1 and 3.5 Å resolution, respectively. In the active state, the BBSome is bound to 5 an Arf-family GTPase (ARL6/BBS3) that recruits the BBSome to ciliary membranes. ARL6 6 recognizes a composite binding site formed by BBS1 and BBS7 that is occluded in the inactive 7 state. Activation requires an unexpected swiveling of the b-propeller domain of BBS1, the key 8 subunit implicated in substrate recognition, which widens a central cavity of the BBSome. 9Structural mapping of disease-causing mutations suggests that pathogenesis predominantly 10 results from disruption of autoinhibition and activation. 11

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supporting

confidence: 52%

Structure and activation mechanism of the BBSome membrane-protein trafficking complex

Singh

Gui

Koh

et al. 2019

Preprint

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“…The strategy for the disruption of genes in hTERT-RPE1 cells (American Type Culture Collection, CRL-4000) by the CRISPR/Cas9 system using homology-independent DNA repair was previously described in detail ((76); also see (12,77,78)). In brief, single-guide RNA (sgRNA) sequences targeting the human ICK gene (see Table S3) were designed using CRISPOR (79).…”

Section: Establishment Of Ick-ko Cell Linesmentioning

confidence: 99%

Anterograde trafficking of ciliary MAP kinase–like ICK/CILK1 by the intraflagellar transport machinery is required for intraciliary retrograde protein trafficking

Nakamura

Noguchi

Takahara

et al. 2020

Journal of Biological Chemistry

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ICK (also known as CILK1) is a MAPK-like kinase localized at the ciliary tip. Its deficiency is known to result in the elongation of cilia, and causes ciliopathies in humans. However, little is known about how ICK is transported to the ciliary tip. We here show that the C-terminal noncatalytic region of ICK interacts with the intraflagellar transport (IFT)-B complex of the IFT machinery, and participates in its transport to the ciliary tip. Furthermore, total internal reflection fluorescence microscopy demonstrated that ICK undergoes bidirectional movement within cilia, similarly to IFT particles. Analysis of ICK-knockout cells demonstrated that ICK deficiency severely impairs the retrograde trafficking of IFT particles and ciliary GPCRs. In addition, we found that in ICK-knockout cells, ciliary proteins are accumulated at the bulged ciliary tip, which appeared to be torn off and release into the environment as an extracellular vesicle. The exogenous expression of various ICK constructs in ICK-knockout cells indicated that the IFT-dependent transport of ICK, as well as its kinase activity and phosphorylation at the canonical TDY motif, is essential for ICK function. Thus, we unequivocally show that ICK transported to the ciliary tip is required for retrograde ciliary protein trafficking and consequently for normal ciliary function.

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“…Another BBS protein complex, the chaperonin-complex, consisting of BBS6 (MKKS), BBS10 and BBS12, assembles the BBSome [ 21 ]. The role of the BBSome was previously suggested to be an adaptor for G-protein coupled receptors (GPCRs) in the process of ciliary delivery, but now studies suggest that the BBSome is mainly involved in retrograde transport and exit of GPCRs from the primary cilium, such as PTCH1, SMO and GRP161 [ 22 , 23 , 24 , 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

BBS Proteins Affect Ciliogenesis and Are Essential for Hedgehog Signaling, but Not for Formation of iPSC-Derived RPE-65 Expressing RPE-Like Cells

Hey

Larsen

Tümer

et al. 2021

IJMS

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Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal dystrophy, renal cysts, obesity and polydactyly. BBS genes have been implicated in ciliogenesis, hedgehog signaling and retinal pigment epithelium maturation. BBS1 and BBS5 are members of the BBSome, implicated in cilia transport of proteins, and BBS10 is a member of the chaperonin-complex, mediating BBSome assembly. In this study, involvement of BBS1, BBS5 and BBS10 in ciliogenesis and hedgehog signaling were investigated in BBS-defective patient fibroblasts as well as in RPE-hTERT cells following siRNA-mediated knockdown of the BBS genes. Furthermore, the ability of BBS1-defective induced pluripotent stem-cells (iPSCs) to differentiate into RPE cells was assessed. We report that cells lacking functional BBS5 or BBS10 have a reduced number of primary cilia, whereas cells lacking functional BBS1 display shorter primary cilia compared to wild-type cells. Hedgehog signaling was substantially impaired and Smoothened, a component of hedgehog signaling, was trapped inside the cilia of the BBS-defective cells, even in the absence of Smoothened agonist. Preliminary results demonstrated the ability of BBS1-defective iPSC to differentiate into RPE-65 expressing RPE-like cells. The BBS1−/−-defective RPE-like cells were less pigmented, compared to RPE-like cells differentiated from control iPSCs, indicating an impact of BBS1 on RPE maturation.

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Requirement of IFT-B–BBSome complex interaction in export of GPR161 from cilia

Cited by 41 publications

References 59 publications

Structure and activation mechanism of the BBSome membrane-protein trafficking complex

Structure and activation mechanism of the BBSome membrane-protein trafficking complex

Anterograde trafficking of ciliary MAP kinase–like ICK/CILK1 by the intraflagellar transport machinery is required for intraciliary retrograde protein trafficking

BBS Proteins Affect Ciliogenesis and Are Essential for Hedgehog Signaling, but Not for Formation of iPSC-Derived RPE-65 Expressing RPE-Like Cells

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