The Host Cell Sulfonation Pathway Contributes to Retroviral Infection at a Step Coincident with Provirus Establishment
The Host Cell Sulfonation Pathway Contributes to Retroviral Infection at a Step Coincident with Provirus Establishment
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DOI：
10.1371/journal.ppat.1000207
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发表时间：
2008-11-01
期刊：
影响因子：
6.7
通讯作者：
Young, John A. T.
中科院分区：
文献类型：
--
作者：
Bruce, James W.;Ahlquist, Paul;Young, John A. T.
逆转录病毒复制导致前病毒建立的早期步骤高度依赖于细胞过程，并且代表病毒特别容易受到抗病毒药物和宿主防御机制的影响的时间。然而，细胞因子所起的作用只是部分了解。为了鉴定参与这些关键步骤的细胞过程，我们使用鼠白血病病毒（MLV）载体对插入诱变的体细胞进行了高容量筛选。这种方法确定了3 '-磷酸腺苷5'-磷酸硫酸合酶1（PAPSS 1）的作用，PAPSS 1是合成PAPS的两种酶之一，PAPS是细胞磺基转移酶催化的所有磺化反应中使用的高能硫酸盐供体。细胞磺化途径的作用，证实了使用化学抑制剂的PAPS酶和细胞磺基转移酶。磺化的要求被映射到MLV前病毒建立期间或之后不久的一个阶段，并影响随后的基因表达从病毒长末端重复序列（LTR）启动子。HIV载体对细胞的感染也显示出高度依赖于细胞磺化途径。这些研究揭示了迄今为止未知的逆转录病毒复制的调节步骤，确定了核基因表达中磺化的新生物学功能，并为HIV/AIDS治疗提供了潜在的有价值的新靶点。
The early steps of retrovirus replication leading up to provirus establishment are highly dependent on cellular processes and represent a time when the virus is particularly vulnerable to antivirals and host defense mechanisms. However, the roles played by cellular factors are only partially understood. To identify cellular processes that participate in these critical steps, we employed a high volume screening of insertionally mutagenized somatic cells using a murine leukemia virus (MLV) vector. This approach identified a role for 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1), one of two enzymes that synthesize PAPS, the high energy sulfate donor used in all sulfonation reactions catalyzed by cellular sulfotransferases. The role of the cellular sulfonation pathway was confirmed using chemical inhibitors of PAPS synthases and cellular sulfotransferases. The requirement for sulfonation was mapped to a stage during or shortly after MLV provirus establishment and influenced subsequent gene expression from the viral long terminal repeat (LTR) promoter. Infection of cells by an HIV vector was also shown to be highly dependent on the cellular sulfonation pathway. These studies have uncovered a heretofore unknown regulatory step of retroviral replication, have defined a new biological function for sulfonation in nuclear gene expression, and provide a potentially valuable new target for HIV/AIDS therapy.