Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling
| Autor: | Bo Lv, Gregory J. Pazour, Paurav B. Desai, Michael W. Stuck |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular BBSome Transcription Genetic Article Protein Structure Secondary 03 medical and health sciences Mice 0302 clinical medicine Ubiquitin Intraflagellar transport Animals Hedgehog Proteins Cilia Hedgehog 030304 developmental biology Cell Line Transformed 0303 health sciences Trafficking biology Chemistry Cilium Ubiquitination Proteins Biological Transport Epithelial Cells Cell Biology Fibroblasts Embryo Mammalian Smoothened Receptor Hedgehog signaling pathway Cell biology Patched-1 Receptor Flagella rab GTP-Binding Proteins biology.protein Signal transduction Smoothened Protein Processing Post-Translational Intracellular 030217 neurology & neurosurgery Signal Transduction Transcription Factors |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Hedgehog signaling involves the dynamic movement of receptors and effectors in and out of cilia. Desai et al. found that the dynamics of Smo are regulated by ubiquitination, which modulates its interaction with the intraflagellar transport system to control ciliary levels of this receptor. 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. |
| Databáze: | OpenAIRE |
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