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Time-resolved proteomic profiling of the ciliary Hedgehog response reveals that GPR161 and PKA undergo regulated co-exit from cilia

Elena A. May, Marian Kalocsay, Inès Galtier D’Auriac, Steven P. Gygi, View ORCID ProfileMaxence V. Nachury, View ORCID ProfileDavid U. Mick
doi: https://doi.org/10.1101/2020.07.29.225797
Elena A. May
1Center of Human and Molecular Biology (ZHMB), Saarland University School of Medicine, Homburg, Germany
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Marian Kalocsay
2Department of Systems Biology, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA
3Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA
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Inès Galtier D’Auriac
4Department of Ophthalmology, University of California San Francisco, CA 94143, USA
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Steven P. Gygi
3Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA
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Maxence V. Nachury
4Department of Ophthalmology, University of California San Francisco, CA 94143, USA
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  • ORCID record for Maxence V. Nachury
  • For correspondence: maxence.nachury@ucsf.edu david.mick@uks.eu
David U. Mick
1Center of Human and Molecular Biology (ZHMB), Saarland University School of Medicine, Homburg, Germany
5Center for Molecular Signaling (PZMS), Department of Medical Biochemistry and Molecular Biology, Saarland University School of Medicine, Homburg, Germany
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  • ORCID record for David U. Mick
  • For correspondence: maxence.nachury@ucsf.edu david.mick@uks.eu
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ABSTRACT

The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the putative phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 29, 2020.
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Time-resolved proteomic profiling of the ciliary Hedgehog response reveals that GPR161 and PKA undergo regulated co-exit from cilia
Elena A. May, Marian Kalocsay, Inès Galtier D’Auriac, Steven P. Gygi, Maxence V. Nachury, David U. Mick
bioRxiv 2020.07.29.225797; doi: https://doi.org/10.1101/2020.07.29.225797
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Time-resolved proteomic profiling of the ciliary Hedgehog response reveals that GPR161 and PKA undergo regulated co-exit from cilia
Elena A. May, Marian Kalocsay, Inès Galtier D’Auriac, Steven P. Gygi, Maxence V. Nachury, David U. Mick
bioRxiv 2020.07.29.225797; doi: https://doi.org/10.1101/2020.07.29.225797

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