Bardet–Biedl syndrome 3 protein promotes ciliary exit of the signaling protein phospholipase D via the BBSome

Liu, Yanxia; Xue, Bin; Sun, Wei-Yue; Wingfield, Jenna L.; Sun, Jun; Wu, Mingfu; Lechtreck, Karl‐Ferdinand; Wu, Zhenlong; Fan, Zhen‐Chuan

doi:10.7554/elife.59119

Cited by 30 publications

(100 citation statements)

References 62 publications

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“…The IFT-B complex contains 16 subunits and mediates anterograde (ciliary base-to-tip direction) trafficking of proteins driven by heterotrimeric kinesin-II, and the IFT-A complex comprises six subunits and mediates retrograde trafficking driven by the dynein-2 motor complex [12,13]. Besides these roles, the IFT-B complex participates in the export of membrane proteins across the ciliary gate in conjunction with the BBSome, which is composed of eight proteins encoded by the causative genes of Bardet-Biedl syndrome (BBS) [14][15][16][17][18]. On the other hand, the IFT-A complex mediates the import of membrane proteins with the aid of the TULP3 adaptor protein [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

CCRK/CDK20 regulates ciliary retrograde protein trafficking via interacting with BROMI/TBC1D32

et al. 2021

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CCRK/CDK20 was reported to interact with BROMI/TBC1D32 and regulate ciliary Hedgehog signaling. In various organisms, mutations in the orthologs of CCRK and those of the kinase ICK/CILK1, which is phosphorylated by CCRK, are known to result in cilia elongation. Furthermore, we recently showed that ICK regulates retrograde ciliary protein trafficking and/or the turnaround event at the ciliary tips, and that its mutations result in the elimination of intraflagellar transport (IFT) proteins that have overaccumulated at the bulged ciliary tips as extracellular vesicles, in addition to cilia elongation. However, how these proteins cooperate to regulate ciliary protein trafficking has remained unclear. We here show that the phenotypes of CCRK-knockout (KO) cells closely resemble those of ICK-KO cells; namely, the overaccumulation of IFT proteins at the bulged ciliary tips, which appear to be eliminated as extracellular vesicles, and the enrichment of GPR161 and Smoothened on the ciliary membrane. The abnormal phenotypes of CCRK-KO cells were rescued by the exogenous expression of wild-type CCRK but not its kinase-dead mutant or a mutant defective in BROMI binding. These results together indicate that CCRK regulates the turnaround process at the ciliary tips in concert with BROMI and probably via activating ICK.

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Section: Introductionmentioning

confidence: 99%

CCRK/CDK20 regulates ciliary retrograde protein trafficking via interacting with BROMI/TBC1D32

et al. 2021

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“…Arf family GTPases associate with the inner membrane via its N-terminal amphipathic helix (Amor et al, 1994;Liu et al, 2010;Zhang et al, 2011b) and their N-terminal 15 residues are found essential for this association (Jin et al, 2010;Liu et al, 2021;Mourão et al, 2014). They were further reported to anchor to the membrane through myristylation on their glycine residue at the second amino acid position and disruption of myristylation by introducing a G2A mutation fully prevents them from associating with the membrane (Fig.…”

Section: Arl3 Gdp Requires Its N-terminal 15 Amino Acids and The G2 Residue For Membrane Association And Diffusion Into Ciliamentioning

confidence: 99%

“…In this study, we identified the BBSome acts as a major ARL3 effector at the ciliary base right above the TZ but not in the cell body of C. reinhardtii. ARL3 mimics other Arf-like GTPases for diffusing into cilia and reversibly binding the ciliary membrane via its N-terminal amphipathic helix and the G2 residue but in a GDP-dependent manner (Liu et al, 2021). Once in cilia, ARL3 undergoes GTPase cycling and the activated ARL3 GTP binds the retrograde IFT-detached and PLD-laden BBSome at the proximal ciliary region right above the TZ and recruits it to diffuse through the TZ for ciliary retrieval.…”

Section: Introductionmentioning

confidence: 99%

ARL3 Mediates BBSome Ciliary Turnover by Promoting Its Outward Diffusion through the Transition Zone

Liu

Sun

Xue

et al. 2021

Preprint

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Ciliary receptors and their certain downstream signaling components undergo intraflagellar transport (IFT) as BBSome cargoes to maintain their ciliary dynamics for sensing and transducing extracellular stimuli inside the cell. Cargo laden BBSomes shed from retrograde IFT at the proximal ciliary region above the transition zone (TZ) followed by diffusing through the TZ for ciliary retrieval, while how the BBSome barrier passage is controlled remains elusive. Here, we show that the BBSome is a major effector of the Arf-like 3 (ARL3) GTPase in Chlamydomonas. Under physiological condition, ARL3GDP binds the membrane for diffusing into and residing in cilia. Following a nucleotide conversion, ARL3GTP dissociates with the ciliary membrane and binds and recruits the IFT-detached and cargo (phospholipase D, PLD)-laden BBSome at the proximal ciliary region to diffuse through the TZ and out of cilia. ARL3 deficiency impairs ciliary signaling, e.g. phototaxis of Chlamydomonas cells, by disrupting BBSome ciliary retrieval, providing a mechanistic understanding behind BBSome ciliary turnover required for ciliary signaling.

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“…With small GTPases, the BBSome assembles into a coat that traffics Golgi vesicles with their valuable cargo to the IFT apparatus where some of the cargo is inserted into the ciliary membrane [36][37][38][39]. G protein coupled protein receptors, such as somatostatin receptor 3 [37] and neuropeptide Y [40], depend upon the BBSome for ciliary localization while other proteins like the signaling protein Phospholipase D depend upon the function of the BBSome to exit the cilium [24,25,41]. Overall, the BBSome has a lot of sway over the ciliary membrane proteome.…”

Section: Bbs Proteinsmentioning

confidence: 99%

“…As discussed above, for some proteins meeting up with IFT trains for entry into the cilium can be orchestrated by the BBSome [36][37][38][39]. Other proteins require the BBSome to pass back through the transition zone to exit the cilium [24,25,41].…”

Section: Transition Zonementioning

confidence: 99%

Using Paramecium as a Model for Ciliopathies

Valentine

Houten

2021

Genes

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Paramecium has served as a model organism for the studies of many aspects of genetics and cell biology: non-Mendelian inheritance, genome duplication, genome rearrangements, and exocytosis, to name a few. However, the large number and patterning of cilia that cover its surface have inspired extraordinary ultrastructural work. Its swimming patterns inspired exquisite electrophysiological studies that led to a description of the bioelectric control of ciliary motion. A genetic dissection of swimming behavior moved the field toward the genes and gene products underlying ciliary function. With the advent of molecular technologies, it became clear that there was not only great conservation of ciliary structure but also of the genes coding for ciliary structure and function. It is this conservation and the legacy of past research that allow us to use Paramecium as a model for cilia and ciliary diseases called ciliopathies. However, there would be no compelling reason to study Paramecium as this model if there were no new insights into cilia and ciliopathies to be gained. In this review, we present studies that we believe will do this. For example, while the literature continues to state that immotile cilia are sensory and motile cilia are not, we will provide evidence that Paramecium cilia are clearly sensory. Other examples show that while a Paramecium protein is highly conserved it takes a different interacting partner or conducts a different ion than expected. Perhaps these exceptions will provoke new ideas about mammalian systems.

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Bardet–Biedl syndrome 3 protein promotes ciliary exit of the signaling protein phospholipase D via the BBSome

Cited by 30 publications

References 62 publications

CCRK/CDK20 regulates ciliary retrograde protein trafficking via interacting with BROMI/TBC1D32

CCRK/CDK20 regulates ciliary retrograde protein trafficking via interacting with BROMI/TBC1D32

ARL3 Mediates BBSome Ciliary Turnover by Promoting Its Outward Diffusion through the Transition Zone

Using Paramecium as a Model for Ciliopathies

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