The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells.
The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells.
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DOI：
10.1038/s41586-023-05912-0
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发表时间：
2023-04
期刊：
影响因子：
64.8
通讯作者：
Lieberman, Judy
中科院分区：
文献类型：
--
作者：
Sen Santara, Sumit;Lee, Dian-Jang;Crespo, Angela;Hu, Jun Jacob;Walker, Caitlin;Ma, Xiyu;Zhang, Ying;Chowdhury, Sourav;Meza-Sosa, Karla F.;Lewandrowski, Mercedes;Zhang, Haiwei;Rowe, Marjorie;McClelland, Arthur;Wu, Hao;Junqueira, Caroline;Lieberman, Judy
当激活的NK细胞受体被触发时，自然杀伤(NK)细胞会杀死感染、转化和应激的细胞。大多数NK细胞和一些天然淋巴样细胞表达活化受体NKp46，该受体由NCR1编码，NCR1是进化最古老的NK细胞受体。阻断NKp46可抑制许多癌症靶点的NK杀伤。虽然已经鉴定了一些具有感染性的NKp46配体，但内源性NKp46细胞表面配体尚不清楚。在这里，我们发现NKp46识别外化的钙网蛋白(ecto-CRT)，它在内质网(ER)应激时从内质网(ER)转移到细胞膜。内质网应激和外源性CRT是化疗诱导的免疫原性细胞死亡、黄病毒感染和衰老的特征。NKp46识别ECTO-CRT的P区可在NK免疫突触中触发NK细胞信号转导和NKp46与ECTO-CRT的结合。编码CRT或CRT抗体的CALR基因的敲除或敲除可抑制NKp46介导的杀伤，而糖基磷脂酰肌醇锚定的CRT的异位表达可增强NKp46介导的杀伤。NCR1基因缺陷的人(和Nrc1基因缺陷的小鼠)NK细胞在杀伤ZIKV感染、内质网应激和衰老细胞以及表达外源CRT的癌细胞方面受到损害。重要的是，NKp46对ecto-CRT的识别控制了小鼠B16黑色素瘤和RAS驱动的肺癌，并增强了肿瘤浸润性NK细胞的脱颗粒和细胞因子的分泌。因此，NKp46将ecto-CRT识别为危险相关的分子模式，消除了内质网应激细胞。
Natural killer (NK) cell kill infected, transformed and stressed cells when an activating NK cell receptor is triggered. Most NK cells and some innate lymphoid cells express the activating receptor NKp46, encoded by NCR1, the most evolutionarily ancient NK cell receptor. Blockage of NKp46 inhibits NK killing of many cancer targets. Although a few infectious NKp46 ligands have been identified, the endogenous NKp46 cell surface ligand is unknown. Here we show that NKp46 recognizes externalized calreticulin (ecto-CRT), which translocates from the endoplasmic reticulum (ER) to the cell membrane during ER stress. ER stress and ecto-CRT are hallmarks of chemotherapy-induced immunogenic cell death, flavivirus infection and senescence. NKp46 recognition of the P domain of ecto-CRT triggers NK cell signalling and NKp46 caps with ecto-CRT in NK immune synapses. NKp46-mediated killing is inhibited by knockout or knockdown of CALR, the gene encoding CRT, or CRT antibodies, and is enhanced by ectopic expression of glycosylphosphatidylinositol-anchored CRT. NCR1)-deficient human (and Nrc1-deficient mouse) NK cells are impaired in the killing of ZIKV-infected, ER-stressed and senescent cells and ecto-CRT-expressing cancer cells. Importantly, NKp46 recognition of ecto-CRT controls mouse B16 melanoma and RAS-driven lung cancers and enhances tumour-infiltrating NK cell degranulation and cytokine secretion. Thus, NKp46 recognition of ecto-CRT as a danger-associated molecular pattern eliminates ER-stressed cells.
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发表时间：
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影响因子：
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影响因子：
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