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Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling

In the absence of Hedgehog ligand, patched-1 (Ptch1) localizes to cilia and prevents ciliary accumulation and activation of smoothened (Smo). Upon ligand binding, Ptch1 is removed from cilia, and Smo is derepressed and accumulates in cilia where it activates signaling. The mechanisms regulating thes...

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Autores principales: Desai, Paurav B., Stuck, Michael W., Lv, Bo, Pazour, Gregory J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337509/
https://www.ncbi.nlm.nih.gov/pubmed/32435793
http://dx.doi.org/10.1083/jcb.201912104
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author Desai, Paurav B.
Stuck, Michael W.
Lv, Bo
Pazour, Gregory J.
author_facet Desai, Paurav B.
Stuck, Michael W.
Lv, Bo
Pazour, Gregory J.
author_sort Desai, Paurav B.
collection PubMed
description In the absence of Hedgehog ligand, patched-1 (Ptch1) localizes to cilia and prevents ciliary accumulation and activation of smoothened (Smo). Upon ligand binding, Ptch1 is removed from cilia, and Smo is derepressed and accumulates in cilia where it activates signaling. The mechanisms regulating these dynamic movements are not well understood, but defects in intraflagellar transport components, including Ift27 and the BBSome, cause Smo to accumulate in cilia without pathway activation. We find that in the absence of ligand-induced pathway activation, Smo is ubiquitinated and removed from cilia, and this process is dependent on Ift27 and BBSome components. Activation of Hedgehog signaling decreases Smo ubiquitination and ciliary removal, resulting in its accumulation. Blocking ubiquitination of Smo by an E1 ligase inhibitor or by mutating two lysine residues in intracellular loop three causes Smo to aberrantly accumulate in cilia without pathway activation. These data provide a mechanism to control Smo’s ciliary level during Hedgehog signaling by regulating the ubiquitination state of the receptor.
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spelling pubmed-73375092021-01-06 Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling Desai, Paurav B. Stuck, Michael W. Lv, Bo Pazour, Gregory J. J Cell Biol Article In the absence of Hedgehog ligand, patched-1 (Ptch1) localizes to cilia and prevents ciliary accumulation and activation of smoothened (Smo). Upon ligand binding, Ptch1 is removed from cilia, and Smo is derepressed and accumulates in cilia where it activates signaling. The mechanisms regulating these dynamic movements are not well understood, but defects in intraflagellar transport components, including Ift27 and the BBSome, cause Smo to accumulate in cilia without pathway activation. We find that in the absence of ligand-induced pathway activation, Smo is ubiquitinated and removed from cilia, and this process is dependent on Ift27 and BBSome components. Activation of Hedgehog signaling decreases Smo ubiquitination and ciliary removal, resulting in its accumulation. Blocking ubiquitination of Smo by an E1 ligase inhibitor or by mutating two lysine residues in intracellular loop three causes Smo to aberrantly accumulate in cilia without pathway activation. These data provide a mechanism to control Smo’s ciliary level during Hedgehog signaling by regulating the ubiquitination state of the receptor. Rockefeller University Press 2020-05-20 /pmc/articles/PMC7337509/ /pubmed/32435793 http://dx.doi.org/10.1083/jcb.201912104 Text en © 2020 Desai et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Desai, Paurav B.
Stuck, Michael W.
Lv, Bo
Pazour, Gregory J.
Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling
title Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling
title_full Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling
title_fullStr Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling
title_full_unstemmed Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling
title_short Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling
title_sort ubiquitin links smoothened to intraflagellar transport to regulate hedgehog signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337509/
https://www.ncbi.nlm.nih.gov/pubmed/32435793
http://dx.doi.org/10.1083/jcb.201912104
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