Primary cilia organize signaling pathways such as vision, olfaction and the Hedgehog developmental pathway. The movements of signaling receptors into, inside and out of cilium are critical for the correct regulation of these pathways, yet our understanding of the basic mechanisms governing signaling receptor trafficking through cilia remains fragmentary. The major goal of this proposal is to study the BBSome, a protein complex that ferries signaling receptors into, inside and out of cilia. The emphasis in this fundin period will be on investigating the turnaround point during which anterograde trains become reconfigured into retrograde trains. While past studies have provided circumstantial evidence for the existence of IFT train turnaround at the tip of cilia, molecular mechanisms are lacking for thi critical step that commits molecules to be removed from cilia. The removal of signaling receptors from cilia may serve to desensitize cilia to specific stimuli and the ciliary export of signaling intermediates such as the Hedgehog effector and transcription Gli3 is required for them to reach their nuclear target. Yet, how molecules are exported from cilia remains elusive. Our preliminary data suggest a testable molecular model for the turnaround point and the assembly of retrograde BBSome/IFT trains. We will test this model using biochemistry and innovative live cell photokinetics assay.

Public Health Relevance

Anomalies of the primary cilium underlie the etiology of a class of disorders presenting with obesity, skeletal abnormalities, kidney cysts and retinal degeneration. The proposal aims to uncover the basic mechanisms governing trafficking of proteins through cilia. If successful, this research program will further our understanding of several clinical modalities and provide novel means for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089933-10
Application #
9671911
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Gindhart, Joseph G
Project Start
2010-04-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Nachury, Maxence V (2018) The molecular machines that traffic signaling receptors into and out of cilia. Curr Opin Cell Biol 51:124-131
Ye, Fan; Nager, Andrew R; Nachury, Maxence V (2018) BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone. J Cell Biol 217:1847-1868
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Nager, Andrew R; Goldstein, Jaclyn S; Herranz-PĂ©rez, Vicente et al. (2017) An Actin Network Dispatches Ciliary GPCRs into Extracellular Vesicles to Modulate Signaling. Cell 168:252-263.e14
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Xu, Zhenjie; Schaedel, Laura; Portran, Didier et al. (2017) Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science 356:328-332

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