Inhibition of T-Cell Receptor-Induced Actin Remodeling and Relocalization of Lck Are Evolutionarily Conserved Activities of Lentiviral Nef Proteins
Inhibition of T-Cell Receptor-Induced Actin Remodeling and Relocalization of Lck Are Evolutionarily Conserved Activities of Lentiviral Nef Proteins
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抑制 T 细胞受体诱导的肌动蛋白重塑和 Lck 重新定位是慢病毒 Nef 蛋白的进化保守活性
DOI：
10.1128/jvi.01423-09
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发表时间：
2009
影响因子：
5.4
通讯作者：
O. Fackler
中科院分区：
文献类型：
--
作者：
J. Rudolph;Nina Eickel;C. Haller;M. Schindler;O. Fackler
摘要 Nef 是人类免疫缺陷病毒（HIV）和猿猴免疫缺陷病毒（SIV）的重要致病因子，可增强病毒在体内的复制。除其他活性外，Nef 通过多种机制影响 T 细胞受体 (TCR) 信号传导。对于 HIV-1 Nef，这些包括免疫突触 (IS) 的组织和功能的改变，例如 Lck 激酶的重新定位，以及 TCR/CD3 复合物 (TCR-CD3) 介导的肌动蛋白重排和酪氨酸磷酸化的早期抑制。尽管大多数 SIV 和 HIV-2 Nef 等位基因（第 2 组）可有效下调细胞表面 TCR-CD3，但这种活性在产生 HIV-1 及其 SIV 对应物（第 1 组）的病毒谱系中丢失。为了解决 TCR-CD3 下调对 Nef 对 TCR 信号启动影响的影响，我们比较了 18 组 1 和 2 组 Nef 蛋白以及具有 TCR-CD3 下调缺陷的 SIV Nef 突变体的活性。我们发现 Lck 亚细胞定位的改变在很大程度上是保守的，并且独立于肌动蛋白重塑抑制或 TCR-CD3 下调而发生。令人惊讶的是，两组 Nef 蛋白也强烈降低了 TCR 诱导的肌动蛋白重塑和 TCR 刺激表面上的酪氨酸磷酸化，而第 2 组 Nef 蛋白的 TCR-CD3 下调能力仅略微提高了这些效果。此外，来自 HIV-1 和 SIV 的 Nef 蛋白减少了受感染的原代人类 T 淋巴细胞和 Raji B 细胞之间的结合，并有效阻止了 IS 处的 F-肌动蛋白极化，而与它们下调 TCR-CD3 的能力无关。这些结果确立了 IS 早期 TCR 信号事件的改变，包括 F-肌动蛋白重塑和 Lck 重新定位，作为高度分化的慢病毒 Nef 蛋白的进化保守活性。
ABSTRACT Nef, an important pathogenicity factor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), elevates virus replication in vivo. Among other activities, Nef affects T-cell receptor (TCR) signaling via several mechanisms. For HIV-1 Nef these include alteration of the organization and function of the immunological synapse (IS) such as relocalization of the Lck kinase, as well as early inhibition of TCR/CD3 complex (TCR-CD3)-mediated actin rearrangements and tyrosine phosphorylation. Although most SIV and HIV-2 Nef alleles (group 2) potently downregulate cell surface TCR-CD3, this activity was lost in the viral lineage that gave rise to HIV-1 and its SIV counterparts (group 1). To address the contribution of TCR-CD3 downregulation to Nef effects on TCR signal initiation, we compared the activities of 18 group 1 and group 2 Nef proteins, as well as SIV Nef mutants with defects in TCR-CD3 downmodulation. We found that alteration of Lck's subcellular localization is largely conserved and occurs independently of actin remodeling inhibition or TCR-CD3 downregulation. Surprisingly, Nef proteins of both groups also strongly reduced TCR-induced actin remodeling and tyrosine phosphorylation on TCR-stimulatory surfaces and TCR-CD3 downmodulation competence by group 2 Nef proteins only slightly elevated these effects. Furthermore, Nef proteins from HIV-1 and SIV reduced conjugation between infected primary human T lymphocytes and Raji B cells and potently prevented F-actin polarization at the IS independently of their ability to downmodulate TCR-CD3. These results establish alterations of early TCR signaling events at the IS, including F-actin remodeling and relocalization of Lck, as evolutionary conserved activities of highly divergent lentiviral Nef proteins.
影响因子：
30.3
作者：
Stolp, Bettina;Reichman-Fried, Michal;Fackler, Oliver T.
通讯作者：
Fackler, Oliver T.
影响因子：
32.4
作者：
Gomez, Timothy S.;McCarney, Sean D.;Burkhardt, Janis K.
通讯作者：
Burkhardt, Janis K.
影响因子：
32.4
作者：
Gomez, Timothy S.;Kumar, Karan;Billadeau, Daniel D.
通讯作者：
Billadeau, Daniel D.