Direct evidence for BBSome-associated intraflagellar transport reveals distinct properties of native mammalian cilia

Williams, Corey; McIntyre, Jeremy C.; Norris, Stephen R.; Jenkins, Paul M.; Zhang, Lian; Pei, Qinglin; Verhey, Kristen J.; Martens, Jeffrey R.

doi:10.1038/ncomms6813

Cited by 157 publications

(192 citation statements)

References 69 publications

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“…In vertebrates, nematodes, and algae, the major pool of BBSome is near the cilium base, but it is also observed to travel with intraflagellar transport particles along the axoneme (18,(31)(32)(33)(34). Absence of detectable TbBBSome in the flagellum itself might reflect technical limitations owing to low abundance of BBSome proteins (32,33).…”

Section: Tbbbsome Associates With Membranes and Vesicles At The Flagementioning

confidence: 99%

Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei

Langousis

Shimogawa

Saada

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cilia (eukaryotic flagella) are present in diverse eukaryotic lineages and have essential motility and sensory functions. The cilium’s capacity to sense and transduce extracellular signals depends on dynamic trafficking of ciliary membrane proteins. This trafficking is often mediated by the Bardet–Biedl Syndrome complex (BBSome), a protein complex for which the precise subcellular distribution and mechanisms of action are unclear. In humans, BBSome defects perturb ciliary membrane protein distribution and manifest clinically as Bardet–Biedl Syndrome. Cilia are also important in several parasites that cause tremendous human suffering worldwide, yet biology of the parasite BBSome remains largely unexplored. We examined BBSome functions in Trypanosoma brucei, a flagellated protozoan parasite that causes African sleeping sickness in humans. We report that T. brucei BBS proteins assemble into a BBSome that interacts with clathrin and is localized to membranes of the flagellar pocket and adjacent cytoplasmic vesicles. Using BBS gene knockouts and a mouse infection model, we show the T. brucei BBSome is dispensable for flagellar assembly, motility, bulk endocytosis, and cell viability but required for parasite virulence. Quantitative proteomics reveal alterations in the parasite surface proteome of BBSome mutants, suggesting that virulence defects are caused by failure to maintain fidelity of the host–parasite interface. Interestingly, among proteins altered are those with ubiquitination-dependent localization, and we find that the BBSome interacts with ubiquitin. Collectively, our data indicate that the BBSome facilitates endocytic sorting of select membrane proteins at the base of the cilium, illuminating BBSome roles at a critical host–pathogen interface and offering insights into BBSome molecular mechanisms.

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Section: Tbbbsome Associates With Membranes and Vesicles At The Flagementioning

confidence: 99%

Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei

Langousis

Shimogawa

Saada

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…To build and maintain a functional cilium, cells rely on intraflagellar transport (IFT; for general reviews, see Ishikawa & Marshall, 2011; Pedersen & Rosenbaum, 2008; Nachury et al , 2010), a bidirectional motility along the MTs of the ciliary axoneme (Kozminski et al , 1993). IFT in Chlamydomonas reinhardtii is dependent on the heterotrimeric kinesin II motor to transport ciliary cargo from the cell body to the tip of the cilium (anterograde IFT) (Kozminski et al , 1995; Cole et al , 1998; Qin et al , 2004; Hao et al , 2011; Craft et al , 2015), but in C. elegans and most likely also vertebrate cilia the heterotrimeric kinesin II cooperates with a homodimeric kinesin II motor for anterograde transport (Snow et al , 2004; Williams et al , 2014; Prevo et al , 2015). At the ciliary tip, exchange of the cargo and remodeling of the IFT complex take place and dynein 2 transports the IFT complex and recycling products back to the cell body (retrograde IFT) (Pazour et al , 1999; Porter et al , 1999; Signor et al , 1999; Qin et al , 2004).…”

Section: Introductionmentioning

confidence: 99%

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

et al. 2016

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Intraflagellar transport (IFT) relies on the IFT complex and is required for ciliogenesis. The IFT‐B complex consists of 9–10 stably associated core subunits and six “peripheral” subunits that were shown to dissociate from the core structure at moderate salt concentration. We purified the six “peripheral” IFT‐B subunits of Chlamydomonas reinhardtii as recombinant proteins and show that they form a stable complex independently of the IFT‐B core. We suggest a nomenclature of IFT‐B1 (core) and IFT‐B2 (peripheral) for the two IFT‐B subcomplexes. We demonstrate that IFT88, together with the N‐terminal domain of IFT52, is necessary to bridge the interaction between IFT‐B1 and B2. The crystal structure of IFT52N reveals highly conserved residues critical for IFT‐B1/IFT‐B2 complex formation. Furthermore, we show that of the three IFT‐B2 subunits containing a calponin homology (CH) domain (IFT38, 54, and 57), only IFT54 binds αβ‐tubulin as a potential IFT cargo, whereas the CH domains of IFT38 and IFT57 mediate the interaction with IFT80 and IFT172, respectively. Crystal structures of IFT54 CH domains reveal that tubulin binding is mediated by basic surface‐exposed residues.

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“…Membrane-embedded receptor proteins at the base of the cilium can dock to the BTC, and are then transported to the tip of the cilium. Although much of what we know about the function of these proteins has been collected from studies on Chlamydomonas and Caenorhabditis elegans, a similar model seems to be operative in mammalian cilia (84) .…”

Section: Intraflagellar Transportmentioning

confidence: 99%

“…This includes membrane-embedded receptors for signal transduction as well as structural components of the cilium. As such, the BBSome is important for the establishment, growth, turnover and functioning of cilia (83,84) . BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9 are part of the BBSome together with the 10 kDa BBSome interacting protein 1 (BBIP1), also referred to as BBIP10 or BBS18 (44,85) .…”

Section: The Bbsomementioning

confidence: 99%

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The cilium: a cellular antenna with an influence on obesity risk

et al. 2016

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Primary cilia are organelles that are present on many different cell types, either transiently or permanently. They play a crucial role in receiving signals from the environment and passing these signals to other parts of the cell. In that way, they are involved in diverse processes such as adipocyte differentiation and olfactory sensation. Mutations in genes coding for ciliary proteins often have pleiotropic effects and lead to clinical conditions, ciliopathies, with multiple symptoms. In this study, we reviewed observations from ciliopathies with obesity as one of the symptoms. It shows that variation in cilia-related genes is itself not a major cause of obesity in the population but may be a part of the multifactorial aetiology of this complex condition. Both common polymorphisms and rare deleterious variants may contribute to the obesity risk. Genotype-phenotype relationships have been noticed. Among the ciliary genes, obesity differs with regard to severity and age of onset, which may relate to the influence of each gene on the balance between pro-and anti-adipogenic processes. Analysis of the function and location of the proteins encoded by these ciliary genes suggests that obesity is more linked to activities at the basal area of the cilium, including initiation of the intraflagellar transport, but less to the intraflagellar transport itself. Regarding the role of cilia, three possible mechanistic processes underlying obesity are described: adipogenesis, neuronal food intake regulation and food odour perception.

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Direct evidence for BBSome-associated intraflagellar transport reveals distinct properties of native mammalian cilia

Cited by 157 publications

References 69 publications

Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei

Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

The cilium: a cellular antenna with an influence on obesity risk

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