Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling
Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling
复制标题
DOI：
10.1016/j.celrep.2020.107809
复制
发表时间：
2020-06-23
期刊：
影响因子：
8.8
通讯作者：
Cunningham, Christian N.
中科院分区：
文献类型：
--
作者：
Holden, Jeffrey K.;Crawford, James J.;Cunningham, Christian N.
转录因子的转录增强相关结构域（TEAD）家族充当Hippo途径的下游效应物雅普和TAZ的受体，以上调参与细胞增殖和存活的多个基因的表达。最近的工作确定了TEAD S-棕榈酰化作为蛋白质稳定性和活性的关键，因为脂质尾部延伸到蛋白质的疏水核心。在这里，我们报告了一种有效的小分子结合TEAD脂质口袋（LP）和破坏TEAD S-棕榈酰化的鉴定和表征。使用各种生物化学，结构和细胞的方法，我们发现，TEAD S-棕榈酰化功能作为TEAD稳态蛋白质水平检查点，这种脂质化的失调影响TEAD转录活性的显性负性方式。此外，我们证明，靶向TEAD LP是一种有前途的治疗策略，用于调节Hippo通路，在小鼠异种移植模型中显示肿瘤停滞。
The transcriptional enhanced associate domain (TEAD) family of transcription factors serves as the receptors for the downstream effectors of the Hippo pathway, YAP and TAZ, to upregulate the expression of multiple genes involved in cellular proliferation and survival. Recent work identified TEAD S-palmitoylation as critical for protein stability and activity as the lipid tail extends into a hydrophobic core of the protein. Here, we report the identification and characterization of a potent small molecule that binds the TEAD lipid pocket (LP) and disrupts TEAD S-palmitoylation. Using a variety of biochemical, structural, and cellular methods, we uncover that TEAD S-palmitoylation functions as a TEAD homeostatic protein level checkpoint and that dysregulation of this lipidation affects TEAD transcriptional activity in a dominant-negative manner. Furthermore, we demonstrate that targeting the TEAD LP is a promising therapeutic strategy for modulating the Hippo pathway, showing tumor stasis in a mouse xenograft model.