小柯机器人

美国波士顿儿童医院Judy Lieberman等研究人员合作发现，NK细胞受体NKp46能识别ER应激细胞上的外化钙网蛋白。2023年4月5日，《自然》杂志在线发表了这项成果。

研究人员表明NKp46能识别外化的钙网蛋白（ecto-CRT），它在ER应激期间从内质网（ER）转运到细胞膜上。ER应激和ecto-CRT是化疗引起的免疫性细胞死亡、黄病毒感染和衰老的标志。NKp46识别ecto-CRT的P结构域引发NK细胞信号，NKp46与ecto-CRT在自然杀伤（NK）免疫突触中盖住。NKp46介导的杀伤被编码CRT的基因CALR或CRT抗体的敲除或敲低所抑制，并被异位表达的糖基磷脂酰肌醇锚定CRT所增强。NCR1缺失的人类（和Nrc1缺失的小鼠）NK细胞对ZIKV感染的、ER应激的和衰老的细胞以及表达ecto-CRT的癌细胞的杀伤力受损。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识别ecto-CRT作为一种危险相关的分子模式，并可以消除ER应激的细胞。

据了解，当激活的NK细胞受体被触发时，NK细胞会杀死感染的、转化的和应激的细胞。大多数NK细胞和一些先天性淋巴细胞表达由NCR1编码的激活受体NKp46，这是演化过程中最古老的NK细胞受体。阻断NKp46会抑制NK对许多癌症目标的杀伤力。尽管一些传染性的NKp46配体已经被确认，但内源性的NKp46细胞表面配体却不为人知。

附：英文原文

Title: The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells

Author: Sen Santara, Sumit, Lee, Dian-Jang, Crespo, ngela, 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

Issue&Volume: 2023-04-05

Abstract: Natural killer (NK) cell kill infected, transformed and stressed cells when an activating NK cell receptor is triggered1. Most NK cells and some innate lymphoid cells express the activating receptor NKp46, encoded by NCR1, the most evolutionarily ancient NK cell receptor2,3. Blockage of NKp46 inhibits NK killing of many cancer targets4. 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 death5,6, flavivirus infection and senescence. NKp46 recognition of the Pdomain 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.

DOI: 10.1038/s41586-023-05912-0

Source: https://www.nature.com/articles/s41586-023-05912-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html