Abstract：
G-protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and regulate various physiological and pathological processes. Despite extensive studies, the roles of GPCRs in mouse embryonic stem cells (mESCs) remain poorly understood. Here, we show that GPR160, a class A member of GPCRs, is dramatically downregulated concurrent with mESC differentiation into embryoid bodies in vitro. Knockdown of Gpr160 leads to downregulation of the expression of pluripotency-associated transcription factors and upregulation of the expression of lineage markers, accompanying with the arrest of the mESC cell-cycle in the G0/G1 phase. RNA-seq analysis shows that GPR160 participates in the JAK/STAT signaling pathway crucial for maintaining ESC stemness, and the knockdown of GPRGpr160 results in the downregulation of STAT3 phosphorylation level, which in turn is partially rescued by colivelin, a STAT3 activator. Consistent with these observations, GPR160 physically interacts with JAK1, and cooperates with leukemia inhibitory factor receptor (LIFR) and gp130 to activate the STAT3 pathway. In summary, our results suggest that GPR160 regulates mESC self-renewal and pluripotency by interacting with the JAK1-LIFR-gp130 complex to mediate the JAK1/STAT3 signaling pathway.
摘要：
G蛋白偶联受体（GPCRs）是跨膜受体的最大家族，调节各种生理和病理过程。尽管进行了广泛的研究,GPCRs在小鼠胚胎干细胞(mESCs)中的作用代表了显著的数据差距.这里,我们证明GPR160是GPCRs的A类成员，在体外mESC分化为胚状体的同时显着下调。敲除GPR160导致多能性相关转录因子表达下调和谱系标记表达上调,伴随着mESC细胞周期停滞在G0/G1期。RNA-seq分析显示GPR160参与JAK/STAT信号通路对维持ESC干性至关重要,GPR160的敲除导致STAT3磷酸化水平下调，而这又是由Colivelin部分解救的,STAT3激活剂。根据这些观察，GPR160与JAK1物理相互作用，并与白血病抑制因子受体（LIFR）和gp130合作激活STAT3途径。总之,我们的结果表明,GPR160通过与JAK1-LIFR-gp130复合物相互作用介导JAK1/STAT3信号通路,从而调节mESC的自我更新和多能性.
