State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
J Cell Biol. 2013 Nov 25;203(4):575-83. doi: 10.1083/jcb.201306012.
The evolutionarily conserved Hedgehog (Hh) signaling pathway is transduced by the Cubitus interruptus (Ci)/Gli family of transcription factors that exist in two distinct repressor (Ci(R)/Gli(R)) and activator (Ci(A)/Gli(A)) forms. Aberrant activation of Hh signaling is associated with various human cancers, but the mechanism through which Ci(R)/Gli(R) properly represses target gene expression is poorly understood. Here, we used Drosophila melanogaster and zebrafish models to define a repressor function of Atrophin (Atro) in Hh signaling. Atro directly bound to Ci through its C terminus. The N terminus of Atro interacted with a histone deacetylase, Rpd3, to recruit it to a Ci-binding site at the decapentaplegic (dpp) locus and reduce dpp transcription through histone acetylation regulation. The repressor function of Atro in Hh signaling was dependent on Ci. Furthermore, Rerea, a homologue of Atro in zebrafish, repressed the expression of Hh-responsive genes. We propose that the Atro-Rpd3 complex plays a conserved role to function as a Ci(R) corepressor.
Hedgehog (Hh) 信号通路在进化上保守，由 Cubitus interruptus (Ci)/Gli 转录因子家族转导，该家族存在两种不同的抑制物 (Ci(R)/Gli(R)) 和激活物 (Ci(A)/Gli(A)) 形式。Hh 信号的异常激活与各种人类癌症有关，但 Ci(R)/Gli(R) 如何正确抑制靶基因表达的机制尚不清楚。在这里，我们使用果蝇和斑马鱼模型来定义 Atrophin (Atro) 在 Hh 信号中的抑制功能。Atro 通过其 C 端直接与 Ci 结合。Atro 的 N 端与组蛋白去乙酰化酶 Rpd3 相互作用，将其招募到 decapentaplegic (dpp) 基因座上的 Ci 结合位点，并通过组蛋白乙酰化调节降低 dpp 转录。Atro 在 Hh 信号中的抑制功能依赖于 Ci。此外，斑马鱼中的 Atro 同源物 Rerea 也抑制了 Hh 反应基因的表达。我们提出 Atro-Rpd3 复合物作为 Ci(R) 核心抑制物发挥保守作用。
