Sewell A K, Price D A, Teisserenc H, Booth B L, Gileadi U, Flavin F M, Trowsdale J, Phillips R E, Cerundolo V
University of Oxford, Nuffield Department of Medicine, Institute of Molecular Medicine, John Radcliffe Hospital, United Kingdom.
J Immunol. 1999 Jun 15;162(12):7075-9.
The proteasome, an essential component of the ATP-dependent proteolytic pathway in eukaryotic cells, is responsible for the degradation of most cellular proteins and is believed to be the main source of MHC class I-restricted antigenic peptides for presentation to CTL. Inhibition of the proteasome by lactacystin or various peptide aldehydes can result in defective Ag presentation, and the pivotal role of the proteasome in Ag processing has become generally accepted. However, recent reports have challenged this observation. Here we examine the processing requirements of two HLA A*0201-restricted epitopes from HIV-1 reverse transcriptase and find that they are produced by different degradation pathways. Presentation of the C-terminal ILKEPVHGV epitope is impaired in ME275 melanoma cells by treatment with lactacystin, and is independent of expression of the IFN-gamma-inducible proteasome beta subunits LMP2 and LMP7. In contrast, both lactacystin treatment and expression of LMP7 induce the presentation of the N-terminal VIYQYMDDL epitope. Consistent with these observations we show that up-regulation of LMP7 by IFN-gamma enhances presentation of the VIYQYMDDL epitope. Hence interplay between constitutive and IFN-gamma-inducible beta-subunits of the proteasome can qualitatively influence Ag presentation. These observations may have relevance to the patterns of immunodominance during the natural course of viral infection.
蛋白酶体是真核细胞中ATP依赖的蛋白水解途径的重要组成部分，负责大多数细胞蛋白的降解，并且被认为是MHC I类限制性抗原肽提呈给细胞毒性T淋巴细胞（CTL）的主要来源。用乳胞素或各种肽醛抑制蛋白酶体可导致抗原提呈缺陷，蛋白酶体在抗原加工中的关键作用已被普遍接受。然而，最近的报道对这一观点提出了挑战。在此，我们研究了来自HIV-1逆转录酶的两个HLA A*0201限制性表位的加工要求，发现它们是由不同的降解途径产生的。用乳胞素处理ME275黑色素瘤细胞会损害C末端ILKEPVHGV表位的提呈，且该表位的提呈与干扰素γ诱导的蛋白酶体β亚基LMP2和LMP7的表达无关。相反，乳胞素处理和LMP7的表达均可诱导N末端VIYQYMDDL表位的提呈。与这些观察结果一致，我们表明干扰素γ上调LMP7可增强VIYQYMDDL表位的提呈。因此，蛋白酶体组成型和干扰素γ诱导型β亚基之间的相互作用可在质量上影响抗原提呈。这些观察结果可能与病毒感染自然过程中的免疫显性模式相关。
