PDF(Pubmed)
Abstract：
UNASSIGNED: Human Herpesvirus 6B (HHV-6B) impedes host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells. Downregulation of MHC-I disengages inhibitory receptors on natural killer (NK) cells, resulting in activation and killing of the target cell if NK cell activating receptors such as NKG2D have engaged stress ligands upregulated on the target cells. Previous work has shown that HHV-6B downregulates three MHC-like stress ligands MICB, ULBP1, and ULBP3, which are recognized by NKG2D. The U20 glycoprotein of the related virus HHV-6A has been implicated in the downregulation of ULBP1, but the precise mechanism remains undetermined.
UNASSIGNED: We set out to investigate the role of HHV-6B U20 in modulating NK cell activity. We used HHV-6B U20 expressed as a recombinant protein or transduced into target cells, as well as HHV-6B infection, to investigate binding interactions with NK cell ligands and receptors and to assess effects on NK cell activation. Small-angle X-ray scattering was used to align molecular models derived from machine-learning approaches.
UNASSIGNED: We demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity. Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels, either at the cell surface or in toto. HHV-6B infection and soluble U20 have the same effect. Transduction of U20 blocks NK cell activation in response to cell-surface ULBP1. Structural modeling of the U20 - ULBP1 complex indicates some similarities to the m152-RAE1γ complex.
UNASSIGNED: We set out to investigate the role of HHV-6B U20 in modulating NK cell activity. We used HHV-6B U20 expressed as a recombinant protein or transduced into target cells, as well as HHV-6B infection, to investigate binding interactions with NK cell ligands and receptors and to assess effects on NK cell activation. Small-angle X-ray scattering was used to align molecular models derived from machine-learning approaches.
UNASSIGNED: We demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity. Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels, either at the cell surface or in toto. HHV-6B infection and soluble U20 have the same effect. Transduction of U20 blocks NK cell activation in response to cell-surface ULBP1. Structural modeling of the U20 - ULBP1 complex indicates some similarities to the m152-RAE1γ complex.
摘要：
■人疱疹病毒6B（HHV-6B）通过下调I类MHC分子（MHC-I）来阻止宿主免疫反应，阻碍抗原呈递到CD8+T细胞。MHC-I的下调释放自然杀伤（NK）细胞上的抑制性受体，如果NK细胞活化受体如NKG2D已经参与在靶细胞上上调的应激配体,则导致靶细胞的活化和杀伤。以前的工作表明，HHV-6B下调三个MHC样应激配体MICB，ULBP1和ULBP3，由NKG2D识别。相关病毒HHV-6A的U20糖蛋白与ULBP1的下调有关，但确切的机制仍未确定。
■我们着手研究HHV-6BU20在调节NK细胞活性中的作用。我们使用HHV-6BU20表达为重组蛋白或转导到靶细胞中，以及HHV-6B感染，研究与NK细胞配体和受体的结合相互作用，并评估对NK细胞活化的影响。小角度X射线散射用于对齐从机器学习方法导出的分子模型。
■我们证明U20以亚微摩尔亲和力直接结合ULBP1。U20的转导降低了NKG2D在细胞表面与ULBP1的结合，但不降低ULBP1蛋白水平。在细胞表面或在toto中。HHV-6B感染和可溶性U20具有相同的作用。U20的转导阻断响应于细胞表面ULBP1的NK细胞活化。U20-ULBP1复合物的结构模型表明与m152-RAE1γ复合物有一些相似之处。
■我们着手研究HHV-6BU20在调节NK细胞活性中的作用。我们使用HHV-6BU20表达为重组蛋白或转导到靶细胞中，以及HHV-6B感染，研究与NK细胞配体和受体的结合相互作用，并评估对NK细胞活化的影响。小角度X射线散射用于对齐从机器学习方法导出的分子模型。
■我们证明U20以亚微摩尔亲和力直接结合ULBP1。U20的转导降低了NKG2D在细胞表面与ULBP1的结合，但不降低ULBP1蛋白水平。在细胞表面或在toto中。HHV-6B感染和可溶性U20具有相同的作用。U20的转导阻断响应于细胞表面ULBP1的NK细胞活化。U20-ULBP1复合物的结构模型表明与m152-RAE1γ复合物有一些相似之处。
