Acetylation modulates prolactin receptor dimerization
Acetylation modulates prolactin receptor dimerization
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DOI：
10.1073/pnas.1010253107
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发表时间：
2010-11-09
影响因子：
11.1
通讯作者：
Chin, Y. Eugene
中科院分区：
文献类型：
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作者：
Ma, Li;Gao, Jin-song;Chin, Y. Eugene
细胞因子激活的受体经历胞外结构域二聚化，这是激活细胞内信号通路所必需的。在这里，我们报道了在催乳素（PRL）处理的细胞中，PRL受体（PRLR）经历了乙酰化依赖的细胞质环二聚化。PRLR募集的creb结合蛋白（CBP）使PRLR细胞质环上随机分布的多个赖氨酸位点乙酰化。两个PRLR单体似乎在从膜近端到膜远端多个部位相互作用，依赖于通过乙酰化中和的多个赖氨酸位点之间的协调。胞质环二聚化的PRLR激活STAT5， STAT5也被CBP乙酰化，并经历乙酰化依赖性二聚化。用去乙酰化酶sirtuin （SIRT）抑制剂烟酰胺或组蛋白去乙酰化酶（HDAC）抑制剂trichostatin A处理细胞可增强PRLR二聚化和随后的信号传导，但表达外源性去乙酰化酶SIRT2或HDAC6可抑制PRLR二聚化和随后的信号传导。我们的研究结果表明，乙酰化和去乙酰化为细胞因子受体PRLR的细胞质环二聚化和随后的STAT5激活提供了变阻剂样调节。
Cytokine-activated receptors undergo extracellular domain dimerization, which is necessary to activate intracellular signaling pathways. Here, we report that in prolactin (PRL)-treated cells, PRL receptor (PRLR) undergoes cytoplasmic loop dimerization that is acetylation-dependent. PRLR-recruited CREB-binding protein (CBP) acetylates multiple lysine sites randomly distributed along the cytoplasmic loop of PRLR. Two PRLR monomers appear to interact with each other at multiple parts from the membrane-proximal region to the membrane-distal region, relying on the coordination among multiple lysine sites neutralized via acetylation. Cytoplasmic loop-dimerized PRLR activates STAT5, which is also acetylated by CBP and undergoes acetylation-dependent dimerization. PRLR dimerization and subsequent signaling are enhanced by treating the cells with deacetylase sirtuin (SIRT) inhibitor nicotinamide or histone deacetylase (HDAC) inhibitor trichostatin A but inhibited by expressing exogenous deacetylase SIRT2 or HDAC6. Our results suggest that acetylation and deacetylation provide the rheostat-like regulation for the cytokine receptor PRLR in its cytoplasmic loop dimerization and subsequent STAT5 activation.