HIV-1 Rev的功能同源物Sam68的显性负性突变体对HIV复制的抑制作用。

Inhibition of HIV replication by dominant negative mutants of Sam68, a functional homolog of HIV-1 Rev.

作者信息

Reddy T R, Xu W, Mau J K, Goodwin C D, Suhasini M, Tang H, Frimpong K, Rose D W, Wong-Staal F

机构信息

Department of Medicine, University of California San Diego, La Jolla 92093, USA.

出版信息

Nat Med. 1999 Jun;5(6):635-42. doi: 10.1038/9479.

DOI:10.1038/9479

PMID:10371501

Abstract

The HIV-1 Rev protein facilitates the nuclear export of mRNA containing the Rev response element (RRE) through binding to the export receptor CRM-1. Here we show that a cellular nuclear protein, Sam68 (Src-associated protein in mitosis), specifically interacts with RRE and can partially substitute for as well as synergize with Rev in RRE-mediated gene expression and virus replication. Differential sensitivity to leptomycin B, an inhibitor of CRM-1, indicates that the export pathways mediated by Rev and Sam68 are distinct. C-terminally deleted mutants of Sam68 inhibited the transactivation of RRE-mediated expression by both wild-type Sam68 and Rev. They were retained in the cytoplasm and impeded the nuclear localization of Rev in co-expressed cells. These mutants also inhibited wild-type HIV-1 replication to the same extent as the RevM10 mutant, and may be useful as anti-viral agents in the treatment of AIDS.

摘要

HIV-1 Rev蛋白通过与输出受体CRM-1结合，促进含有Rev反应元件（RRE）的mRNA的核输出。我们在此表明，一种细胞核蛋白Sam68（有丝分裂中的Src相关蛋白）能特异性地与RRE相互作用，并且在RRE介导的基因表达和病毒复制中，它可以部分替代Rev并与Rev协同作用。对CRM-1抑制剂雷帕霉素B的不同敏感性表明，由Rev和Sam68介导的输出途径是不同的。Sam68的C末端缺失突变体抑制了野生型Sam68和Rev对RRE介导的表达的反式激活。它们滞留在细胞质中，并在共表达细胞中阻碍Rev的核定位。这些突变体还与RevM10突变体一样，同等程度地抑制野生型HIV-1复制，并且可能作为抗艾滋病的抗病毒药物。