Ruegg C L, Strand M
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
J Immunol. 1990 May 15;144(10):3928-35.
We have previously shown that a synthetic peptide containing env residues 581-597 from HIV-1 inhibits lymphoproliferation of human PBMC. We have investigated the molecular mechanism(s) by which this HIV-1-derived peptide inhibits CD3-mediated signal transduction. We show that the peptide containing residues 581-597 from the HIV-1 transmembrane protein gp41 specifically inhibited the intracellular Ca2+ influx in Jurkat cells stimulated by the mAb OKT3 whereas it had no effect on the production of inositol triphosphate. In addition, the peptide inhibited protein kinase C (pkC)-mediated phosphorylation of the CD3 gamma-chain in intact cells and directly inhibited partially purified pkC. The inhibition was noncompetitive with respect to the substrates histone and ATP and independent of the regulatory domain of the enzyme. Furthermore, the peptide required internalization for inhibitory activity because no inhibition of lymphoproliferation was observed when cells were treated with peptide at 4 degrees C. Based on these results obtained with the peptide aa581-597, we postulate that the transmembrane protein gp41 of HIV-1 may inhibit pkC activity and thus block pkC-dependent immune function contributing to the immunosuppression of HIV-1-infected individuals.
我们之前已经表明，一种含有来自HIV-1的env残基581 - 597的合成肽可抑制人外周血单核细胞（PBMC）的淋巴细胞增殖。我们研究了这种源自HIV-1的肽抑制CD3介导的信号转导的分子机制。我们发现，含有HIV-1跨膜蛋白gp41残基581 - 597的肽特异性抑制了单克隆抗体OKT3刺激的Jurkat细胞内的Ca2+内流，而对肌醇三磷酸的产生没有影响。此外，该肽抑制完整细胞中蛋白激酶C（PKC）介导的CD3γ链的磷酸化，并直接抑制部分纯化的PKC。这种抑制作用对底物组蛋白和ATP而言是非竞争性的，且与该酶的调节结构域无关。此外，该肽需要内化才能发挥抑制活性，因为在4℃用肽处理细胞时未观察到淋巴细胞增殖受到抑制。基于用肽aa581 - 597获得的这些结果，我们推测HIV-1的跨膜蛋白gp41可能抑制PKC活性，从而阻断PKC依赖的免疫功能，这导致了HIV-1感染个体的免疫抑制。
