Mele Anthony R, Marino Jamie, Chen Kenneth, Pirrone Vanessa, Janetopoulos Chris, Wigdahl Brian, Klase Zachary, Nonnemacher Michael R
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania.
Traffic. 2018 Apr 30. doi: 10.1111/tra.12578.
The human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat) protein functions both intracellularly and extracellularly. Intracellularly, the main function is to enhance transcription of the viral promoter. However, this process only requires a small amount of intracellular Tat. The majority of Tat is secreted through an unconventional mechanism by binding to phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P ), a phospholipid in the inner leaflet of the plasma membrane that is required for secretion. This interaction is mediated by the basic domain of Tat (residues 48-57) and a conserved tryptophan (residue 11). After binding to PtdIns(4,5)P , Tat secretion diverges into multiple pathways, which we categorized as oligomerization-mediated pore formation, spontaneous translocation and incorporation into exosomes. Extracellular Tat has been shown to be neurotoxic and toxic to other cells of the central nervous system (CNS) and periphery, able to recruit immune cells to the CNS and cerebrospinal fluid, and alter the gene expression and morphology of uninfected cells. The effects of extracellular Tat have been examined in HIV-1-associated neurocognitive disorders (HAND); however, only a small number of studies have focused on the mechanisms underlying Tat secretion. In this review, the molecular mechanisms of Tat secretion will be examined in a variety of biologically relevant cell types.
1型人类免疫缺陷病毒（HIV-1）转录反式激活因子（Tat）蛋白在细胞内和细胞外均有功能。在细胞内，其主要功能是增强病毒启动子的转录。然而，这一过程仅需要少量的细胞内Tat。大多数Tat通过一种非常规机制分泌，即通过与磷脂酰肌醇-4,5-二磷酸（PtdIns(4,5)P）结合，PtdIns(4,5)P是质膜内小叶中的一种磷脂，是分泌所必需的。这种相互作用由Tat的碱性结构域（第48 - 57位氨基酸残基）和一个保守的色氨酸（第11位氨基酸残基）介导。与PtdIns(4,5)P结合后，Tat分泌进入多种途径，我们将其分类为寡聚化介导的孔形成、自发易位和外泌体掺入。细胞外Tat已被证明对中枢神经系统（CNS）和外周的其他细胞具有神经毒性和毒性，能够将免疫细胞募集到CNS和脑脊液中，并改变未感染细胞的基因表达和形态。细胞外Tat的作用已在HIV-1相关神经认知障碍（HAND）中进行了研究；然而，只有少数研究关注Tat分泌的潜在机制。在这篇综述中，将在多种生物学相关细胞类型中研究Tat分泌的分子机制。
