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Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling.

Authors
  • Desai, Paurav B1
  • Stuck, Michael W1
  • Lv, Bo1
  • Pazour, Gregory J1
  • 1 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
Type
Published Article
Journal
The Journal of Cell Biology
Publisher
The Rockefeller University Press
Publication Date
Jul 06, 2020
Volume
219
Issue
7
Identifiers
DOI: 10.1083/jcb.201912104
PMID: 32435793
Source
Medline
Language
English
License
Unknown

Abstract

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. © 2020 Desai et al.

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