Ring Finger Protein 11 Inhibits Melanocortin 3 and 4 Receptor Signaling
Ring Finger Protein 11 Inhibits Melanocortin 3 and 4 Receptor Signaling
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DOI：
10.3389/fendo.2016.00109
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发表时间：
2016-08-08
影响因子：
5.2
通讯作者：
Biebermann, Heike
中科院分区：
文献类型：
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作者：
Mueller, Anne;Niederstadt, Lars;Biebermann, Heike
通过G蛋白偶联受体（GPCR）、黑皮质素受体4（MC 4 R）和黑皮质素受体3（MC 3R）的完整黑皮质素信号传导对于体重维持至关重要。到目前为止，黑皮质素信号和下丘脑炎症之间的联系还没有报道。使用双分子荧光互补文库筛选，我们确定了这些受体的新的相互作用伙伴，环指蛋白11（RNF 11）。RNF 11参与A20复合物的构建，该复合物参与减少肿瘤坏死因子α（TNF α）诱导的NF κ B信号传导，这是下丘脑炎症的重要途径。用高脂饮食（HFD）处理3天的小鼠表现出下丘脑Rnf 11表达增加的趋势，如HFD下的其他炎症标志物所示。此外，尽管总受体表达不变，但证明了通过共表达RNF 11将GS介导的MC 3/4 R信号传导强烈降低至20-40%。MC 3R的细胞表面表达不受影响，但与RNF 11共表达导致MC 4 R显著降低至61%。HFD、炎症和代谢之间的联系机制仍有部分了解。在这项研究中，一个新的轴之间的信号传导的特定体重调节GPCR和参与下丘脑炎症的因素。
Intact melanocortin signaling via the G protein-coupled receptors (GPCRs), melanocortin receptor 4 (MC4R), and melanocortin receptor 3 (MC3R) is crucial for body weight maintenance. So far, no connection between melanocortin signaling and hypothalamic inflammation has been reported. Using a bimolecular fluorescence complementation library screen, we identified a new interaction partner for these receptors, ring finger protein 11 (RNF11). RNF11 participates in the constitution of the A20 complex that is involved in reduction of tumor necrosis factor alpha (TNF alpha)-induced NF kappa B signaling, an important pathway in hypothalamic inflammation. Mice treated with high-fat diet (HFD) for 3 days demonstrated a trend toward an increase in hypothalamic Rnf11 expression, as shown for other inflammatory markers under HFD. Furthermore, Gs-mediated signaling of MC3/4R was demonstrated to be strongly reduced to 20-40% by co-expression of RNF11 despite unchanged total receptor expression. Cell surface expression was not affected for MC3R but resulted in a significant reduction of MC4R to 61% by co-expression with RNF11. Mechanisms linking HFD, inflammation, and metabolism remain partially understood. In this study, a new axis between signaling of specific body weight regulating GPCRs and factors involved in hypothalamic inflammation is suggested.