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Immunosuppression by Mutated Calreticulin Released from Malignant Cells.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-27 , DOI: 10.1016/j.molcel.2019.11.004 Peng Liu 1 , Liwei Zhao 2 , Friedemann Loos 1 , Caroline Marty 3 , Wei Xie 1 , Isabelle Martins 1 , Sylvie Lachkar 1 , Bo Qu 4 , Emmanuelle Waeckel-Énée 5 , Isabelle Plo 3 , William Vainchenker 3 , Franck Perez 6 , David Rodriguez 7 , Carlos López-Otin 8 , Peter van Endert 5 , Laurence Zitvogel 4 , Oliver Kepp 1 , Guido Kroemer 9
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-27 , DOI: 10.1016/j.molcel.2019.11.004 Peng Liu 1 , Liwei Zhao 2 , Friedemann Loos 1 , Caroline Marty 3 , Wei Xie 1 , Isabelle Martins 1 , Sylvie Lachkar 1 , Bo Qu 4 , Emmanuelle Waeckel-Énée 5 , Isabelle Plo 3 , William Vainchenker 3 , Franck Perez 6 , David Rodriguez 7 , Carlos López-Otin 8 , Peter van Endert 5 , Laurence Zitvogel 4 , Oliver Kepp 1 , Guido Kroemer 9
Affiliation
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Mutations affecting exon 9 of the CALR gene lead to the generation of a C-terminally modified calreticulin (CALR) protein that lacks the KDEL endoplasmic reticulum (ER) retention signal and consequently mislocalizes outside of the ER where it activates the thrombopoietin receptor in a cell-autonomous fashion, thus driving myeloproliferative diseases. Here, we used the retention using selective hooks (RUSH) assay to monitor the trafficking of CALR. We found that exon-9-mutated CALR was released from cells in response to the biotin-mediated detachment from its ER-localized hook, in vitro and in vivo. Cellular CALR release was confirmed in suitable mouse models bearing exon-9-mutated hematopoietic systems or tumors. Extracellular CALR mediated immunomodulatory effects and inhibited the phagocytosis of dying cancer cells by dendritic cells (DC), thereby suppressing antineoplastic immune responses elicited by chemotherapeutic agents or by PD-1 blockade. Altogether, our results demonstrate paracrine immunosuppressive effects for exon-9-mutated CALR.
中文翻译：
从恶性细胞释放的突变的钙网蛋白的免疫抑制。
影响CALR基因外显子9的突变导致C末端修饰的钙网蛋白（CALR）蛋白的生成，该蛋白缺少KDEL内质网（ER）保留信号，因此在ER外部错位，从而激活了细胞中的血小板生成素受体-自主时尚，从而引发骨髓增生性疾病。在这里，我们使用选择性钩子（RUSH）检测法来保留以监测CALR的贩运。我们发现，外显子9突变的CALR在体内和体外响应于生物素介导的其ER定位钩所引起的脱离而从细胞中释放出来。在携带外显子9突变的造血系统或肿瘤的合适小鼠模型中证实了细胞CALR释放。细胞外CALR介导的免疫调节作用并抑制树突状细胞（DC）对垂死的癌细胞的吞噬作用，从而抑制由化学治疗剂或PD-1阻滞引起的抗肿瘤免疫应答。总之，我们的结果证明了外显子9突变的CALR的旁分泌免疫抑制作用。
更新日期：2019-11-28
中文翻译：
从恶性细胞释放的突变的钙网蛋白的免疫抑制。
影响CALR基因外显子9的突变导致C末端修饰的钙网蛋白（CALR）蛋白的生成，该蛋白缺少KDEL内质网（ER）保留信号，因此在ER外部错位，从而激活了细胞中的血小板生成素受体-自主时尚，从而引发骨髓增生性疾病。在这里，我们使用选择性钩子（RUSH）检测法来保留以监测CALR的贩运。我们发现，外显子9突变的CALR在体内和体外响应于生物素介导的其ER定位钩所引起的脱离而从细胞中释放出来。在携带外显子9突变的造血系统或肿瘤的合适小鼠模型中证实了细胞CALR释放。细胞外CALR介导的免疫调节作用并抑制树突状细胞（DC）对垂死的癌细胞的吞噬作用，从而抑制由化学治疗剂或PD-1阻滞引起的抗肿瘤免疫应答。总之，我们的结果证明了外显子9突变的CALR的旁分泌免疫抑制作用。
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