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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Tumor-associated calreticulin variants functionally compromise the peptide loading complex and impair its recruitment of MHC-I
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Tumor-associated calreticulin variants functionally compromise the peptide loading complex and impair its recruitment of MHC-I

机译：肿瘤相关的钙网蛋白变体在功能上损害了肽加载复合物并损害了其对MHC-1的募集

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Major histocompatibility complex-I–β2m dimers (MHC-I) bind peptides derived from intracellular proteins, enabling the immune system to distinguish between normal cells and those expressing pathogen-derived or mutant proteins. The peptides bind to MHC-I in the endoplasmic reticulum (ER), and this binding is facilitated by the peptide loading complex (PLC), which contains calreticulin (CRT). CRT associates with MHC-I via a conserved glycan present on MHC-I and recruits it to the PLC for peptide binding. Somatic frameshift mutations in CRT (CRT-FS) drive the proliferation of a subset of myeloproliferative neoplasms, which are chronic blood tumors. All CRT-FS proteins have a C-terminal sequence lacking the normal ER-retention signal and possessing a net negative charge rather than the normal positive charge. We characterized the effect of CRT-FS on antigen presentation by MHC-I in human cells. Our results indicate that CRT-FS cannot mediate CRT's peptide loading function in the PLC. Cells lacking CRT exhibited reduced surface MHC-I levels, consistent with reduced binding of high-affinity peptides, and this was not reversed by CRT-FS expression. CRT-FS was secreted and not detectably associated with the PLC, leading to poor MHC-I recruitment, although CRT-FS could still associate with MHC-I in a glycan-dependent manner. The addition of an ER-retention sequence to CRT-FS restored its association with the PLC but did not rescue MHC-I recruitment or its surface expression, indicating that the CRT-FS mutants functionally compromise the PLC. MHC-I down-regulation permits tumor cells to evade immune surveillance, and these findings may therefore be relevant for designing effective immunotherapies for managing myeloproliferative neoplasms.
机译：主要的组织相容性复合物I-β2m二聚体（MHC-1）结合细胞内蛋白衍生的肽，使免疫系统能够区分正常细胞和表达病原体衍生蛋白或突变蛋白的细胞。肽与内质网（ER）中的MHC-1结合，而这种结合可通过含有钙网蛋白（CRT）的肽负载复合物（PLC）来促进。 CRT通过MHC-1上存在的保守聚糖与MHC-1缔合，并将其募集到PLC进行肽结合。 CRT（CRT-FS）中的体细胞移码突变驱动一部分骨髓增生性肿瘤的增殖，这是慢性血液肿瘤。所有CRT-FS蛋白的C端序列均缺乏正常的ER保留信号，并且具有净负电荷而不是正常的正电荷。我们表征了CRT-FS对人细胞中MHC-1抗原呈递的影响。我们的结果表明，CRT-FS无法在PLC中介导CRT的肽加载功能。缺乏CRT的细胞表现出降低的表面MHC-1水平，这与高亲和力肽的结合减少一致，并且CRT-FS的表达并未逆转。尽管CRT-FS仍然可以以聚糖依赖的方式与MHC-1结合，但CRT-FS却被分泌出来并且与PLC不可检测地结合，从而导致MHC-1募集不良。向CRT-FS添加ER保留序列可恢复其与PLC的关联，但不能挽救MHC-1募集或其表面表达，这表明CRT-FS突变体在功能上损害了PLC。 MHC-1下调使肿瘤细胞能够逃避免疫监视，因此这些发现可能与设计用于控制骨髓增生性肿瘤的有效免疫疗法有关。

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