Baltes Jennifer, Larsen Jakob Vejby, Radhakrishnan Karthikeyan, Geumann Constanze, Kratzke Manuel, Petersen Claus Munck, Schu Peter
Georg-August University Göttingen, Department for Cellular Biochemistry, Humboldtallee 23, D-37073 Göttingen, Germany.
MIND Center Department of Biomedicine, Ole Worms Allé 3, Aarhus University, 8000 Aarhus, Denmark.
J Cell Sci. 2014 Aug 15;127(Pt 16):3477-87. doi: 10.1242/jcs.146886. Epub 2014 Jun 13.
Here, we describe altered sorting of sortilin in adipocytes deficient for the σ1B-containing AP-1 complex, leading to the inhibition of adipogenesis. The AP-1 complex mediates protein sorting between the trans-Golgi network and endosomes. Vertebrates express three AP1 σ1 subunit isoforms - σ1A, σ1B and σ1C (also known as AP1S1, AP1S2 and AP1S3, respectively). σ1B-deficient mice display impaired recycling of synaptic vesicles and lipodystrophy. Here, we show that sortilin is overexpressed in adipose tissue from σ1B(-/-) mice, and that its overexpression in wild-type cells is sufficient to suppress adipogenesis. σ1B-specific binding of sortilin requires the sortilin DxxD-x12-DSxxxL motif. σ1B deficiency does not lead to a block of sortilin transport out of a specific organelle, but the fraction that reaches lysosomes is reduced. Sortilin binds to the receptor DLK1, an inhibitor of adipocyte differentiation, and the overexpression of sortilin prevents DLK1 downregulation, leading to enhanced inhibition of adipogenesis. DLK1 and sortilin expression are not increased in the brain tissue of σ1B(-/-) mice, although this is the tissue with the highest expression of σ1B and sortilin. Thus, adipose-tissue-specific and σ1B-dependent routes for the transport of sortilin exist and are involved in the regulation of adipogenesis and adipose-tissue mass.
在此，我们描述了在缺乏含σ1B的AP-1复合物的脂肪细胞中sortilin分选的改变，这导致脂肪生成受到抑制。AP-1复合物介导反式高尔基体网络和内体之间的蛋白质分选。脊椎动物表达三种AP1 σ1亚基异构体——σ1A、σ1B和σ1C（也分别称为AP1S1、AP1S2和AP1S3）。缺乏σ1B的小鼠表现出突触小泡循环受损和脂肪营养不良。在此，我们表明sortilin在σ1B(-/-)小鼠的脂肪组织中过表达，并且其在野生型细胞中的过表达足以抑制脂肪生成。sortilin与σ1B的特异性结合需要sortilin DxxD-x12-DSxxxL基序。σ1B缺乏不会导致sortilin从特定细胞器的转运受阻，但到达溶酶体的部分减少。Sortilin与脂肪细胞分化抑制剂受体DLK1结合，sortilin的过表达阻止DLK1下调，导致对脂肪生成的抑制增强。尽管脑组织是σ1B和sortilin表达最高的组织，但在σ1B(-/-)小鼠的脑组织中DLK1和sortilin的表达并未增加。因此，存在脂肪组织特异性且依赖于σ1B的sortilin转运途径，其参与脂肪生成和脂肪组织质量的调节。
