Bifurcating action of Smoothened in Hedgehog signaling is mediated by Dlg5.
Bifurcating action of Smoothened in Hedgehog signaling is mediated by Dlg5.
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DOI：
10.1101/gad.252676.114
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发表时间：
2015-02-01
影响因子：
10.5
通讯作者：
Beachy PA
中科院分区：
文献类型：
--
作者：
Chong YC;Mann RK;Zhao C;Kato M;Beachy PA
Chong等人在生物化学筛选中鉴定了Dlg 5（大圆盘，同源物5），其蛋白质优先与活化的Smoothened（Smo）相互作用。Smo-Dlg 5相互作用的破坏导致Hedgehog（Hh）途径反应减弱，而对Smo纤毛蓄积无显著影响。他们的其他发现表明，Smo活性在Hh反应中存在分歧，其中一个Dlg 5独立臂用于抑制Gli阻遏物形成，第二个臂涉及Smo与Dlg 5相互作用以激活Gli。Hedgehog（Hh）蛋白信号与其受体Patched的结合诱导初级纤毛内的七次跨膜蛋白Smoothened（Smo）和纤毛尖端处的锌指转录因子Gli 2的积累，最终导致Gli-mediated的核基因表达变化。然而，从Smo到Gli 2的通路激活的机制尚不清楚。为了阐明这一机制，我们确定了Dlg 5（光盘大，同源5）在生化筛选蛋白质，优先与激活Smo相互作用。我们发现，Smo-Dlg 5相互作用的破坏或内源性Dlg 5的消耗导致Hh途径反应减弱，而对Smo纤毛积累没有显著影响。我们还发现Dlg 5定位于基底体，在那里它与另一个通路组分Kif 7相关联。我们表明，DLG 5是所需的HH诱导的富集Kif 7和Gli 2的纤毛的尖端，但Gpr 161退出纤毛和随之而来的抑制Gli 3加工成其阻遏物的形式是不稳定的。我们的研究结果表明，在Hh反应的Smo活性的分叉，与Dlg 5独立的手臂抑制Gli阻遏物的形成和第二个手臂涉及Smo与Dlg 5的Gli激活的相互作用。
Chong et al. identified Dlg5 (Discs large, homolog 5) in a biochemical screen for proteins that preferentially interact with activated Smoothened (Smo). Disruption of Smo–Dlg5 interactions leads to diminished Hedgehog (Hh) pathway response without a significant impact on Smo ciliary accumulation. Their additional findings suggest a bifurcation of Smo activity in Hh response, with a Dlg5-independent arm for suppression of Gli repressor formation and a second arm involving Smo interaction with Dlg5 for Gli activation. Binding of the Hedgehog (Hh) protein signal to its receptor, Patched, induces accumulation of the seven-pass transmembrane protein Smoothened (Smo) within the primary cilium and of the zinc finger transcription factor Gli2 at the ciliary tip, resulting ultimately in Gli-mediated changes in nuclear gene expression. However, the mechanism by which pathway activation is communicated from Smo to Gli2 is not known. In an effort to elucidate this mechanism, we identified Dlg5 (Discs large, homolog 5) in a biochemical screen for proteins that preferentially interact with activated Smo. We found that disruption of Smo–Dlg5 interactions or depletion of endogenous Dlg5 leads to diminished Hh pathway response without a significant impact on Smo ciliary accumulation. We also found that Dlg5 is localized at the basal body, where it associates with another pathway component, Kif7. We show that Dlg5 is required for Hh-induced enrichment of Kif7 and Gli2 at the tip of the cilium but is dispensable for Gpr161 exit from the cilium and the consequent suppression of Gli3 processing into its repressor form. Our findings suggest a bifurcation of Smo activity in Hh response, with a Dlg5-independent arm for suppression of Gli repressor formation and a second arm involving Smo interaction with Dlg5 for Gli activation.
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