Chen Alan C, Donovan Adriana, Ned-Sykes Renee, Andrews Nancy C
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC 27705;
Division of Pharmacology and Preclinical Biology, Scholar Rock, Cambridge, MA 02142;
Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11714-9. doi: 10.1073/pnas.1511701112. Epub 2015 Aug 31.
Transferrin receptor 1 (Tfr1) facilitates cellular iron uptake through receptor-mediated endocytosis of iron-loaded transferrin. It is expressed in the intestinal epithelium but not involved in dietary iron absorption. To investigate its role, we inactivated the Tfr1 gene selectively in murine intestinal epithelial cells. The mutant mice had severe disruption of the epithelial barrier and early death. There was impaired proliferation of intestinal epithelial cell progenitors, aberrant lipid handling, increased mRNA expression of stem cell markers, and striking induction of many genes associated with epithelial-to-mesenchymal transition. Administration of parenteral iron did not improve the phenotype. Surprisingly, however, enforced expression of a mutant allele of Tfr1 that is unable to serve as a receptor for iron-loaded transferrin appeared to fully rescue most animals. Our results implicate Tfr1 in homeostatic maintenance of the intestinal epithelium, acting through a role that is independent of its iron-uptake function.
转铁蛋白受体1(Tfr1)通过受体介导的内吞作用促进细胞对铁的摄取,该过程涉及铁负载的转铁蛋白。它在肠道上皮细胞中表达,但不参与膳食铁的吸收。为了研究其作用,我们在小鼠肠道上皮细胞中选择性地使Tfr1基因失活。突变小鼠的上皮屏障严重受损并过早死亡。肠道上皮细胞祖细胞的增殖受损,脂质处理异常,干细胞标志物的mRNA表达增加,并且许多与上皮-间质转化相关的基因被显著诱导。注射铁剂并不能改善这种表型。然而,令人惊讶的是,强制表达一种不能作为铁负载转铁蛋白受体的Tfr1突变等位基因似乎能完全挽救大多数动物。我们的结果表明,Tfr1通过独立于其铁摄取功能的作用参与肠道上皮的稳态维持。