INSERM UMR1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Imagine Institute, 75015, Paris, France.
Faculté de médecine Paris Descartes, Université Paris Descartes, 75015, Paris, France.
Nat Commun. 2017 Nov 21;8(1):1640. doi: 10.1038/s41467-017-01601-5.
Dendritic cells (DC) have the unique ability to present exogenous antigens via the major histocompatibility complex class I pathway to stimulate naive CD8 T cells. In DCs with a non-functional mutation in Unc93b1 (3d mutation), endosomal acidification, phagosomal maturation, antigen degradation, antigen export to the cytosol and the function of the store-operated-Ca-entry regulator STIM1 are impaired. These defects result in compromised antigen cross-presentation and anti-tumor responses in 3d-mutated mice. Here, we show that UNC93B1 interacts with the calcium sensor STIM1 in the endoplasmic reticulum, a critical step for STIM1 oligomerization and activation. Expression of a constitutively active STIM1 mutant, which no longer binds UNC93B1, restores antigen degradation and cross-presentation in 3d-mutated DCs. Furthermore, ablation of STIM1 in mouse and human cells leads to a decrease in cross-presentation. Our data indicate that the UNC93B1 and STIM1 cooperation is important for calcium flux and antigen cross-presentation in DCs.
树突状细胞 (DC) 具有通过主要组织相容性复合体 I 途径呈现外源性抗原以刺激幼稚 CD8 T 细胞的独特能力。在 Unc93b1（3d 突变）中具有功能缺失突变的 DC 中，内体酸化、吞噬体成熟、抗原降解、抗原输出到细胞质以及储存操作-Ca-进入调节剂 STIM1 的功能受损。这些缺陷导致 3d 突变小鼠的抗原交叉呈递和抗肿瘤反应受损。在这里，我们表明 UNC93B1 在 ER 中与钙传感器 STIM1 相互作用，这是 STIM1 寡聚化和激活的关键步骤。表达不再与 UNC93B1 结合的组成型激活 STIM1 突变体可恢复 3d 突变的 DC 中的抗原降解和交叉呈递。此外，在小鼠和人细胞中敲除 STIM1 会导致交叉呈递减少。我们的数据表明 UNC93B1 和 STIM1 的合作对于 DC 中的钙通量和抗原交叉呈递很重要。
