BCR ubiquitination controls BCR-mediated antigen processing and presentation
BCR ubiquitination controls BCR-mediated antigen processing and presentation
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DOI：
10.1182/blood-2006-05-025338
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发表时间：
2006-12-15
期刊：
影响因子：
20.3
通讯作者：
Drake, James R.
中科院分区：
文献类型：
--
作者：
Drake, Lisa;McGovern-Brindisi, Erica M.;Drake, James R.
BCR介导的抗原加工发生在免疫相关抗原浓度下，并取决于抗原-BCR（Ag-BCR）复合物向II类含多泡体（MVB）（称为MIIC）的运输。然而，银-BCR复合物运输到MIIC和在MIIC内的分子机制还不清楚。相比之下，表皮生长因子受体（EGFR）向MVB和MVB内的运输是通过一种充分表征的遍在蛋白依赖性机制发生的，该机制可通过蛋白酶体活性的急性抑制而被阻断。使用高度表征的抗原特异性模型系统，确定了正常（即未转化）B细胞IgM BCR的免疫球蛋白重链亚基是泛素化的。此外，蛋白酶体活性的急性抑制延迟泛素化配体-BCR复合物的形成，改变内化的Ag-BCR复合物的细胞内运输，并选择性地阻断BCR介导的同源抗原的加工和呈递，而不抑制通过液相内吞内化的非同源抗原的内吞、加工和呈递。这些结果表明，Ag-BCR复合物向MVB样抗原加工区室和MVB样抗原加工区室内的运输通过与EGFR所用的分子机制相似的分子机制发生，并建立了EGFR作为进一步分析Ag-BCR向MIIC和MIIC内运输的范例。（血。2006;108：4086-4093）（c）2006年由美国血液学学会。
BCR-mediated antigen processing occurs at immunologically relevant antigen concentrations and hinges on the trafficking of antigen-BCR (Ag-BCR) complexes to class II-containing multivesicular bodies (MVBs) termed MIICs. However, the molecular mechanism underlying the trafficking of Ag-BCR complexes to and within MIICs is not well understood. In contrast, the trafficking of the epidermal growth factor receptor (EGFR) to and within MVBs occurs via a well-characterized ubiquitin-dependent mechanism, which is blocked by acute inhibition of proteasome activity. Using a highly characterized antigen-specific model system, it was determined that the immunoglobulin heavy chain subunit of the IgM BCR of normal (ie, nontransformed) B cells is ubiquitinated. Moreover, acute inhibition of proteasome activity delays the formation of ubiquitinated ligand-BCR complexes, alters the intracellular trafficking of internalized Ag-BCR complexes, and selectively blocks the BCR-mediated processing and presentation of cognate antigen, without inhibiting the endocytosis, processing, and presentation of non-cognate antigen internalized by fluid-phase endocytosis. These results demonstrate that the trafficking of Ag-BCR complexes to and within MVB-like antigen processing compartments occurs via a molecular mechanism with similarities to that used by the EGFR, and establishes the EGFR as a paradigm for the further analysis of Ag-BCR trafficking to and within MIICs. (Blood. 2006;108:4086-4093)(c) 2006 by The American Society of Hematology.