Department of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, USA.
PLoS Biol. 2013;11(5):e1001571. doi: 10.1371/journal.pbio.1001571. Epub 2013 May 28.
Transferrin Receptor (TfR1) is the cell-surface receptor that regulates iron uptake into cells, a process that is fundamental to life. However, TfR1 also facilitates the cellular entry of multiple mammalian viruses. We use evolutionary and functional analyses of TfR1 in the rodent clade, where two families of viruses bind this receptor, to mechanistically dissect how essential housekeeping genes like TFR1 successfully balance the opposing selective pressures exerted by host and virus. We find that while the sequence of rodent TfR1 is generally conserved, a small set of TfR1 residue positions has evolved rapidly over the speciation of rodents. Remarkably, all of these residues correspond to the two virus binding surfaces of TfR1. We show that naturally occurring mutations at these positions block virus entry while simultaneously preserving iron-uptake functionalities, both in rodent and human TfR1. Thus, by constantly replacing the amino acids encoded at just a few residue positions, TFR1 divorces adaptation to ever-changing viruses from preservation of key cellular functions. These dynamics have driven genetic divergence at the TFR1 locus that now enforces species-specific barriers to virus transmission, limiting both the cross-species and zoonotic transmission of these viruses.
转铁蛋白受体 1（TfR1）是一种细胞表面受体，调节铁进入细胞，这是生命的基本过程。然而，TfR1 也促进了多种哺乳动物病毒进入细胞。我们使用啮齿动物分支中的 TfR1 的进化和功能分析，其中有两类病毒结合该受体，从机制上剖析了像 TFR1 这样的基本管家基因如何成功地平衡宿主和病毒施加的相反选择压力。我们发现，尽管啮齿动物 TfR1 的序列通常是保守的，但一小部分 TfR1 残基位置在啮齿动物的物种形成过程中迅速进化。值得注意的是，所有这些残基都对应于 TfR1 的两个病毒结合表面。我们表明，这些位置的自然发生突变会阻止病毒进入，同时保留铁摄取功能，无论是在啮齿动物还是人类 TfR1 中。因此，通过不断替换仅几个残基位置编码的氨基酸，TFR1 将对不断变化的病毒的适应与对关键细胞功能的保护分离开来。这些动态导致了 TFR1 基因座的遗传分化，现在对病毒传播施加了种特异性屏障，限制了这些病毒的跨种和人畜共患传播。
