A single nucleotide polymorphism in tetherin promotes retrovirus restriction in vivo.
A single nucleotide polymorphism in tetherin promotes retrovirus restriction in vivo.
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DOI：
10.1371/journal.ppat.1002596
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Santiago ML
中科院分区：
文献类型：
--
作者：
Barrett BS;Smith DS;Li SX;Guo K;Hasenkrug KJ;Santiago ML
Tetherin是一种从啮齿动物到人类表达的具有不寻常拓扑结构的膜蛋白，其在感染细胞的表面上积累包膜病毒颗粒。然而，在体内急性逆转录病毒感染过程中，这种“拴系”活性是促进还是限制逆转录病毒的传播是有争议的。我们在这里报告的NZW/LacJ（NZW）小鼠的Tetherin基因的单核苷酸多态性的鉴定，突变的经典ATG起始位点GTG。从下游ATG翻译NZW Tetherin删除了保守的双酪氨酸内体分选基序，导致与C57 BL/6（B6）Tetherin相比，体外细胞表面表达更高，对Friend逆转录病毒释放的抑制作用更强。对（B6×NZW）F1杂交小鼠的分析表明，NZW小鼠中Tetherin细胞表面表达的增加是体内隐性性状。使用经典的遗传回交方法，NZW Tetherin表达与Friend逆转录病毒复制和发病机制降低密切相关。然而，在B6 Apobec 3/Rfv 3抗性的背景下未观察到NZW Tetherin的保护作用。这些发现确定了哺乳动物宿主内的第一个功能性Tetherin多态性，表明Tetherin细胞表面表达是逆转录病毒限制的关键参数，并表明存在限制因子层次结构以抵抗体内致病性逆转录病毒感染。人类和小鼠基因组的重要部分由逆转录病毒序列组成，揭示了哺乳动物宿主和逆转录病毒之间长期冲突的历史，导致宿主限制因子的进化。限制性因子基因的核苷酸突变提供了这一正在进行的进化过程的一瞥，但直接探测逆转录病毒感染期间限制性因子突变的影响的研究是有限的。在这项研究中，我们确定了一个单核苷酸突变的Tetherin主机限制性基因，导致Tetherin保留在细胞表面上。在细胞培养中，Tetherin在受感染的细胞表面积累病毒体并阻止病毒体释放，但一些研究表明Tetherin可能促进细胞间病毒传播。我们的研究表明，Tetherin多态性抑制逆转录病毒复制和疾病。因此，增加的Tetherin细胞表面表达增强了Tetherin的抗逆转录病毒功能。这些结果可能对利用Tetherin的生物学来控制HIV-1等致病性逆转录病毒具有重要意义。
Tetherin is a membrane protein of unusual topology expressed from rodents to humans that accumulates enveloped virus particles on the surface of infected cells. However, whether this ‘tethering’ activity promotes or restricts retroviral spread during acute retrovirus infection in vivo is controversial. We report here the identification of a single nucleotide polymorphism in the Tetherin gene of NZW/LacJ (NZW) mice that mutated the canonical ATG start site to GTG. Translation of NZW Tetherin from downstream ATGs deleted a conserved dual-tyrosine endosomal sorting motif, resulting in higher cell surface expression and more potent inhibition of Friend retrovirus release compared to C57BL/6 (B6) Tetherin in vitro. Analysis of (B6×NZW)F1 hybrid mice revealed that increased Tetherin cell surface expression in NZW mice is a recessive trait in vivo. Using a classical genetic backcrossing approach, NZW Tetherin expression strongly correlated with decreased Friend retrovirus replication and pathogenesis. However, the protective effect of NZW Tetherin was not observed in the context of B6 Apobec3/Rfv3 resistance. These findings identify the first functional Tetherin polymorphism within a mammalian host, demonstrate that Tetherin cell surface expression is a key parameter for retroviral restriction, and suggest the existence of a restriction factor hierarchy to counteract pathogenic retrovirus infections in vivo. Significant portions of the human and mouse genomes are comprised of retroviral sequences, revealing the long history of conflict between mammalian hosts and retroviruses that led to the evolution of host restriction factors. Nucleotide mutations in restriction factor genes provide a glimpse of this ongoing evolutionary process, but studies that directly probe the impact of restriction factor mutations during retrovirus infection are limited. In this study, we identified a single nucleotide mutation in the Tetherin host restriction gene that resulted in retention of Tetherin on the cell surface. In cell culture, Tetherin accumulates virions on the infected cell surface and prevents virion release, but some studies suggested that Tetherin might facilitate cell-to-cell virus spread. Our studies reveal that the Tetherin polymorphism inhibits retrovirus replication and disease. Thus, increased Tetherin cell surface expression enhanced the antiretroviral function of Tetherin. These results could have important implications in harnessing the biology of Tetherin for controlling pathogenic retroviruses such as HIV-1.
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