The primary cilium, a """"""""signaling antenna"""""""" projecting at the surface of the cell, is required for the transduction of Hedgehog and planar cell polarity signals and concentrates many signaling receptors on its surface. Furthermore, ciliary dysfunction leads to obesity, retinal degeneration and kidney cysts in the inherited disorder Bardet-Biedl Syndrome (BBS). Yet, the mechanisms of signaling receptor trafficking to the ciliary membrane are not understood. We recently discovered a stable complex of seven BBS proteins, that we named the BBSome and have implicated in vesicular trafficking to the cilium based on its functional interaction with Rab8, a GTPase with a well-established trafficking function whose manipulations directly impact cilium growth. Here, we advance the hypothesis that the BBSome sorts specific transmembrane proteins to the primary cilium. In this research proposal, we will dissect BBSome function within the context of vesicular transport to the cilium through the following aims: 1- Identify the transmembrane proteins transported by the BBSome towards the cilium. Known ciliary transmembrane proteins will be tested for a BBSome requirement in their trafficking to cilia and we will establish a time-resolved trafficking assay to identify the donor compartment from which the BBSome selects its cargoes. 2- Dissect the mechanisms of BBSome targeting to cilia. We will assay the function of BBSome-binding proteins in mediating the recruitment of the BBSome to cilia. 3- Characterize the functional interplay between the BBSome and Rab8. In preliminary studies, we have found that the BBSome interacts with Rabin8, the GDP/GTP exchange factor for Rab. Here, we will seek to understand how the BBSome modulates the activity and localization of Rabin8 to enable Rab8 entry into the cilium. In conclusion, our model for BBSome function has significant implications for the etiology of Bardet-Biedl syndrome: in a model where the BBSome targets specific signaling receptors to the cilium, each individual symptom of BBS results from the disruption of a specific ciliary signaling pathway.

Public Health Relevance

Anomalies of the primary cilium underly the etiology of polycystic kidney disease, the most frequent autosomal dominant hereditary disorder. More broadly, cilia are thought to represent the unifying causality for a class of disorders presenting with obesity, skeletal abnormalities and retinal degeneration. Thus, gaining an understanding of the basic mechanisms that build the primary cilium has the potential to further our understanding of numerous clinical modalities and possibly lead to the development of therapeutics for multiple indications.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Membrane Biology and Protein Processing (MBPP)
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Gindhart, Joseph G
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Stanford University
Schools of Medicine
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See, Stephanie K; Hoogendoorn, Sascha; Chung, Andrew H et al. (2016) Cytoplasmic Dynein Antagonists with Improved Potency and Isoform Selectivity. ACS Chem Biol 11:53-60
Langousis, Gerasimos; Shimogawa, Michelle M; Saada, Edwin A et al. (2016) Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei. Proc Natl Acad Sci U S A 113:632-7
Breslow, David K; Nachury, Maxence V (2015) Analysis of soluble protein entry into primary cilia using semipermeabilized cells. Methods Cell Biol 127:203-21
Mick, David U; Rodrigues, Rachel B; Leib, Ryan D et al. (2015) Proteomics of Primary Cilia by Proximity Labeling. Dev Cell 35:497-512
Nachury, Maxence V (2014) How do cilia organize signalling cascades? Philos Trans R Soc Lond B Biol Sci 369:
Scheidecker, Sophie; Etard, Christelle; Pierce, Nathan W et al. (2014) Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J Med Genet 51:132-6
Mourão, André; Nager, Andrew R; Nachury, Maxence V et al. (2014) Structural basis for membrane targeting of the BBSome by ARL6. Nat Struct Mol Biol 21:1035-41
Liew, Gerald M; Ye, Fan; Nager, Andrew R et al. (2014) The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Dev Cell 31:265-78
Aguilar, Andrea; Becker, Lars; Tedeschi, Thomas et al. (2014) Α-tubulin K40 acetylation is required for contact inhibition of proliferation and cell-substrate adhesion. Mol Biol Cell 25:1854-66
Howes, Stuart C; Alushin, Gregory M; Shida, Toshinobu et al. (2014) Effects of tubulin acetylation and tubulin acetyltransferase binding on microtubule structure. Mol Biol Cell 25:257-66

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