Genetic inactivation of the translin/trax microRNA-degrading enzyme phenocopies the robust adiposity induced by Translin (Tsn) deletion
Genetic inactivation of the translin/trax microRNA-degrading enzyme phenocopies the robust adiposity induced by Translin (Tsn) deletion
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DOI：
10.1016/j.molmet.2020.101013
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发表时间：
2020-10-01
影响因子：
8.1
通讯作者：
Baraban, Jay M.
中科院分区：
文献类型：
--
作者：
Fu, Xiuping;Shah, Aparna P.;Baraban, Jay M.
目的：小鼠中Translin （Tsn）的缺失会引起异常的代谢谱，其特征是肥胖、正常体重和葡萄糖耐量。Translin （TN）蛋白和它的伙伴trax （TX）组成了TN/TX微rna降解酶。由于microRNA系统在调节代谢中起着突出的作用，我们推断Tsn KO小鼠显示的代谢谱可能反映了microRNA信号通路的失调。方法：为了验证这一假设，我们在编码TX的基因Tsnax中插入了一个突变E126A，该突变消除了TN/TX复合物的微rna降解酶活性。此外，为了帮助确定驱动肥胖表型的细胞类型，我们还生成了具有Tsn或Tsnax的卷曲等位基因的小鼠。结果：在Tsnax中引入E126A突变不影响TN或TX蛋白的表达或它们的共沉淀。此外，这些小鼠显示出与Tsn缺失诱导的microrna相匹配的选择性增加，证实了Tsnax的突变使TN/TX复合物的microrna降解活性失活。纯合Tsnax （E126A）突变的小鼠显示出与Tsn KO小鼠非常相似的代谢谱。从脂肪细胞或肝细胞（两种候选细胞类型）中选择性删除Tsn或Tsnax，不会表现出具有组成性Tsn缺失或Tsnax （E126A）突变的小鼠所显示的肥胖升高的表型。此外，Tsn在成年期的全身性条件缺失并不会导致肥胖增加。结论：综上所述，这些发现表明，发育过程中TN/TX微rna降解酶的失活是驱动Tsn KO小鼠表现出强健肥胖的必要条件。(C) 2020作者。Elsevier GmbH出版。
Objective: Deletion of Translin (Tsn) from mice induces an unusual metabolic profile characterized by robust adiposity, normal body weight and glucose tolerance. Translin (TN) protein and its partner, trax (TX), form the TN/TX microRNA-degrading enzyme. Since the microRNA system plays a prominent role in regulating metabolism, we reasoned that the metabolic profile displayed by Tsn KO mice might reflect dysregulation of microRNA signaling.Methods: To test this hypothesis, we inserted a mutation, E126A, in Tsnax, the gene encoding TX, that abolishes the microRNA-degrading enzymatic activity of the TN/TX complex. In addition, to help define the cell types that drive the adiposity phenotype, we have also generated mice with floxed alleles of Tsn or Tsnax.Results: Introduction of the E126A mutation in Tsnax does not impair expression of TN or TX proteins or their co-precipitation. Furthermore, these mice display selective increases in microRNAs that match those induced by Tsn deletion, confirming that this mutation in Tsnax inactivates the microRNA-degrading activity of the TN/TX complex. Mice homozygous for the Tsnax (E126A) mutation display a metabolic profile that closely mimics that of Tsn KO mice. Selective deletion of Tsn or Tsnax from either adipocytes or hepatocytes, two candidate cell types, does not phenocopy the elevated adiposity displayed by mice with constitutive Tsn deletion or the Tsnax (E126A) mutation. Furthermore, global, conditional deletion of Tsn in adulthood does not elicit increased adiposity.Conclusion: Taken together, these findings indicate that inactivation of the TN/TX microRNA-degrading enzyme during development is necessary to drive the robust adiposity displayed by Tsn KO mice. (C) 2020 The Author(s). Published by Elsevier GmbH.