Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells
Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells
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DOI：
10.1073/pnas.1507981112
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发表时间：
2015-08-18
影响因子：
11.1
通讯作者：
Roche, Paul A.
中科院分区：
文献类型：
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作者：
Cho, Kyung-Jin;Walseng, Even;Roche, Paul A.
抗原呈递细胞（APCs）对MHC II类（MHC-II）依赖抗原呈递进行了仔细控制，以实现免疫反应的特异性；抗原肽- mhc - ii复合物（pMHC-II）的调节组装和降解是这种控制的一个方面。在这项研究中，我们研究了泛素化在apc中调节pMHC-II的生物合成、内吞作用、再循环和周转中的作用。通过使用从MHC-II泛素化突变小鼠获得的APCs，我们发现泛素化不影响树突状细胞（dc）中pMHC-II的形成，但它确实促进了新合成的pMHC-II的后续降解。dc或B细胞的急性激活终止MHC-II E3泛素连接酶March-I的表达，并阻止pMHC-II泛素化。最重要的是，这种变化导致dc和B细胞表面非常有效地回收pMHC-II，从而阻止内化pMHC-II靶向溶酶体降解。生化和功能分析证实，MHC-II泛素突变dc或野生型dc的急性激活抑制了pMHC-II的转化。这些研究表明，急性APC激活通过促进pMHC-II的有效循环和阻止内化pMHC-II的溶酶体靶向，从而阻断pMHC-II的泛素依赖性周转，从而增强pMHC-II的稳定性，从而有效地将抗原呈递到CD4 T细胞。
MHC class II (MHC-II)-dependent antigen presentation by antigen-presenting cells (APCs) is carefully controlled to achieve specificity of immune responses; the regulated assembly and degradation of antigenic peptide-MHC-II complexes (pMHC-II) is one aspect of such control. In this study, we have examined the role of ubiquitination in regulating pMHC-II biosynthesis, endocytosis, recycling, and turnover in APCs. By using APCs obtained from MHC-II ubiquitination mutant mice, we find that whereas ubiquitination does not affect pMHC-II formation in dendritic cells (DCs), it does promote the subsequent degradation of newly synthesized pMHC-II. Acute activation of DCs or B cells terminates expression of the MHC-II E3 ubiquitin ligase March-I and prevents pMHC-II ubiquitination. Most importantly, this change results in very efficient pMHC-II recycling from the surface of DCs and B cells, thereby preventing targeting of internalized pMHC-II to lysosomes for degradation. Biochemical and functional assays confirmed that pMHC-II turnover is suppressed in MHC-II ubiquitin mutant DCs or by acute activation of wild-type DCs. These studies demonstrate that acute APC activation blocks the ubiquitin-dependent turnover of pMHC-II by promoting efficient pMHC-II recycling and preventing lysosomal targeting of internalized pMHC-II, thereby enhancing pMHC-II stability for efficient antigen presentation to CD4 T cells.