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Gli2 acetylation at lysine 757 regulates hedgehog-dependent transcriptional output by preventing its promoter occupancy.

Coni S, Antonucci L, D'Amico D, Di Magno L, Infante P, De Smaele E, Giannini G, Di Marcotullio L, Screpanti I, Gulino A, Canettieri G - PLoS ONE (2013)

Bottom Line: Consistently, in sections of developing mouse cerebella Gli2 acetylation correlates with the activation status of Hedgehog signaling.Mechanistically, acetylation at K757 prevents Gli2 entry into chromatin.Together, these data illustrate a novel mechanism of regulation of the Hh signaling whereby, in concert with Gli1, Gli2 acetylation functions as a key transcriptional checkpoint in the control of morphogen-dependent processes.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 7277, Inserm 1091, Institut de Biologie Valrose (iBV), Centre de Biochimie, Nice, France.

ABSTRACT
The morphogenic Hedgehog (Hh) signaling regulates postnatal cerebellar development and its aberrant activation leads to medulloblastoma. The transcription factors Gli1 and Gli2 are the activators of Hh pathway and their function is finely controlled by different covalent modifications, such as phosphorylation and ubiquitination. We show here that Gli2 is endogenously acetylated and that this modification represents a key regulatory step for Hedgehog signaling. The histone acetyltransferase (HAT) coactivator p300, but not other HATs, acetylates Gli2 at the conserved lysine K757 thus inhibiting Hh target gene expression. By generating a specific anti acetyl-Gli2(Lys757) antisera we demonstrated that Gli2 acetylation is readily detectable at endogenous levels and is attenuated by Hh agonists. Moreover, Gli2 K757R mutant activity is higher than wild type Gli2 and is no longer enhanced by Hh agonists, indicating that acetylation represents an additional level of control for signal dependent activation. Consistently, in sections of developing mouse cerebella Gli2 acetylation correlates with the activation status of Hedgehog signaling. Mechanistically, acetylation at K757 prevents Gli2 entry into chromatin. Together, these data illustrate a novel mechanism of regulation of the Hh signaling whereby, in concert with Gli1, Gli2 acetylation functions as a key transcriptional checkpoint in the control of morphogen-dependent processes.

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Related in: MedlinePlus

Model of acetylation-dependent control of Gli activity.Following Hh/Ptch interaction, Smo triggers a signaling cascade leading to Gli2 deacetylation and to the inhibition of the βTrCP-regulated balance between Gli2R and full length Gli2 (Gli2A). Both events contributes to the early signal-dependent activation of the Hh pathway. Once activated, Gli2 promotes transcription of Gli1, whose activity is also regulated by Hh-induced HDAC1-mediated deacetylation, thus generating a positive feedback loop (late activation).
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pone-0065718-g005: Model of acetylation-dependent control of Gli activity.Following Hh/Ptch interaction, Smo triggers a signaling cascade leading to Gli2 deacetylation and to the inhibition of the βTrCP-regulated balance between Gli2R and full length Gli2 (Gli2A). Both events contributes to the early signal-dependent activation of the Hh pathway. Once activated, Gli2 promotes transcription of Gli1, whose activity is also regulated by Hh-induced HDAC1-mediated deacetylation, thus generating a positive feedback loop (late activation).

Mentions: In conclusion, these data illustrate a novel mechanism of regulation of the Hh signaling, where acetylation of Gli2 at lysine 757 functions as a critical regulated step, controlling the activation status of Hh pathway. We suggest that this mechanism contributes to the early regulatory events immediately downstream of Smo (i.e. cleavage-dependent balance between Gli2A and Gli2R), and is functionally coordinated with Gli1 acetylation, which represents a late regulated step of Hedgehog pathway activation (Fig. 5).


Gli2 acetylation at lysine 757 regulates hedgehog-dependent transcriptional output by preventing its promoter occupancy.

Coni S, Antonucci L, D'Amico D, Di Magno L, Infante P, De Smaele E, Giannini G, Di Marcotullio L, Screpanti I, Gulino A, Canettieri G - PLoS ONE (2013)

Model of acetylation-dependent control of Gli activity.Following Hh/Ptch interaction, Smo triggers a signaling cascade leading to Gli2 deacetylation and to the inhibition of the βTrCP-regulated balance between Gli2R and full length Gli2 (Gli2A). Both events contributes to the early signal-dependent activation of the Hh pathway. Once activated, Gli2 promotes transcription of Gli1, whose activity is also regulated by Hh-induced HDAC1-mediated deacetylation, thus generating a positive feedback loop (late activation).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675076&req=5

pone-0065718-g005: Model of acetylation-dependent control of Gli activity.Following Hh/Ptch interaction, Smo triggers a signaling cascade leading to Gli2 deacetylation and to the inhibition of the βTrCP-regulated balance between Gli2R and full length Gli2 (Gli2A). Both events contributes to the early signal-dependent activation of the Hh pathway. Once activated, Gli2 promotes transcription of Gli1, whose activity is also regulated by Hh-induced HDAC1-mediated deacetylation, thus generating a positive feedback loop (late activation).
Mentions: In conclusion, these data illustrate a novel mechanism of regulation of the Hh signaling, where acetylation of Gli2 at lysine 757 functions as a critical regulated step, controlling the activation status of Hh pathway. We suggest that this mechanism contributes to the early regulatory events immediately downstream of Smo (i.e. cleavage-dependent balance between Gli2A and Gli2R), and is functionally coordinated with Gli1 acetylation, which represents a late regulated step of Hedgehog pathway activation (Fig. 5).

Bottom Line: Consistently, in sections of developing mouse cerebella Gli2 acetylation correlates with the activation status of Hedgehog signaling.Mechanistically, acetylation at K757 prevents Gli2 entry into chromatin.Together, these data illustrate a novel mechanism of regulation of the Hh signaling whereby, in concert with Gli1, Gli2 acetylation functions as a key transcriptional checkpoint in the control of morphogen-dependent processes.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 7277, Inserm 1091, Institut de Biologie Valrose (iBV), Centre de Biochimie, Nice, France.

ABSTRACT
The morphogenic Hedgehog (Hh) signaling regulates postnatal cerebellar development and its aberrant activation leads to medulloblastoma. The transcription factors Gli1 and Gli2 are the activators of Hh pathway and their function is finely controlled by different covalent modifications, such as phosphorylation and ubiquitination. We show here that Gli2 is endogenously acetylated and that this modification represents a key regulatory step for Hedgehog signaling. The histone acetyltransferase (HAT) coactivator p300, but not other HATs, acetylates Gli2 at the conserved lysine K757 thus inhibiting Hh target gene expression. By generating a specific anti acetyl-Gli2(Lys757) antisera we demonstrated that Gli2 acetylation is readily detectable at endogenous levels and is attenuated by Hh agonists. Moreover, Gli2 K757R mutant activity is higher than wild type Gli2 and is no longer enhanced by Hh agonists, indicating that acetylation represents an additional level of control for signal dependent activation. Consistently, in sections of developing mouse cerebella Gli2 acetylation correlates with the activation status of Hedgehog signaling. Mechanistically, acetylation at K757 prevents Gli2 entry into chromatin. Together, these data illustrate a novel mechanism of regulation of the Hh signaling whereby, in concert with Gli1, Gli2 acetylation functions as a key transcriptional checkpoint in the control of morphogen-dependent processes.

Show MeSH
Related in: MedlinePlus