TEA domain (TEAD) transcription factors bind to the coactivators YAP and TAZ and regulate the transcriptional output of the Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches a fatty acid, palmitate, to cysteine residues and regulates protein trafficking, membrane localization and signaling activities. Using activity-based chemical probes, we discovered that human TEADs possess intrinsic palmitoylating enzyme–like activities and undergo autopalmitoylation at evolutionarily conserved cysteine residues under physiological conditions. We determined the crystal structures of lipid-bound TEADs and found that the lipid chain of palmitate inserts into a conserved deep hydrophobic pocket. Strikingly, palmitoylation did not alter TEAD's localization, but it was required for TEAD's binding to YAP and TAZ and was dispensable for its binding to the Vgll4 tumor suppressor. Moreover, palmitoylation-deficient TEAD mutants impaired TAZ-mediated muscle differentiation in vitro and tissue overgrowth mediated by the Drosophila YAP homolog Yorkie in vivo. Our study directly links autopalmitoylation to the transcriptional regulation of the Hippo pathway.

TEA域（TEAD）转录因子与辅助激活剂YAP和TAZ结合并调节Hippo途径的转录输出，在器官大小控制和肿瘤发生中起关键作用。蛋白S-棕榈酰化将脂肪酸棕榈酸酯连接到半胱氨酸残基上，并调节蛋白运输，膜定位和信号传导活性。使用基于活动的化学探针，我们发现人TEAD具有内在的棕榈酰化酶样活性，并且在生理条件下，在进化上保守的半胱氨酸残基上经历了自身的棕榈酰化。我们确定了脂质结合的TEADs的晶体结构，并发现棕榈酸酯的脂质链插入到一个保守的深疏水袋中。令人惊讶的是，棕榈酰化并没有改变TEAD的定位，但这是TEAD'所必需的 可以与YAP和TAZ结合，并且可以与Vgll4肿瘤抑制剂结合。此外，棕榈酰化缺陷的TEAD突变体损害了TAZ介导的肌肉分化在体外通过介导和组织过度生长果蝇YAP同源约克体内。我们的研究直接将自身棕榈酸酯化与河马途径的转录调控联系起来。