Wijesuriya Tishani Methsala, De Ceuninck Leentje, Masschaele Delphine, Sanderson Matthea R, Carias Karin Vanessa, Tavernier Jan, Wevrick Rachel
Department of Medical Genetics, University of Alberta, Edmonton T6G 2H7, Canada.
Department of Biochemistry, VIB Center for Medical Biotechnology and Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium.
Hum Mol Genet. 2017 Nov 1;26(21):4215-4230. doi: 10.1093/hmg/ddx311.
In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS.
在普拉德-威利综合征（PWS）中，肥胖是由大脑中食欲控制通路的破坏引起的。两个PWS候选基因编码MAGEL2和Necdin，它们是相关的黑色素瘤抗原蛋白，可组装成泛素化复合物。缺乏Magel2的小鼠肥胖，且下丘脑阿黑皮素原神经元对瘦素不敏感，提示瘦素受体（LepR）活性失调。Magel2基因敲除小鼠的下丘脑LepR较少，且调节LepR加工的泛素通路蛋白（Rnf41、Usp8和Stam1）水平发生改变。MAGEL2增加了LepR在细胞表面的丰度并减少其降解。LepR与Necdin相互作用，Necdin与MAGEL2相互作用，MAGEL2与RNF41和USP8形成复合物。MAGEL2的MAGE同源结构域中的突变抑制RNF41的稳定性，并阻止MAGEL2介导的细胞表面LepR增加。因此，MAGEL2和Necdin共同通过动态的泛素依赖性途径控制LepR的分选和降解。MAGEL2和Necdin的缺失可能使LepR与泛素化途径解偶联，为PWS中的肥胖提供了一种细胞机制。
