2019年7月出版的《自然—免疫学》杂志，发表了美国丹娜-法伯癌症研究所Laurie H. Glimcher研究组的一项成果。他们发现了内质网应激传感器IRE1部分通过调节c-Myc激活自然杀伤免疫细胞。

研究表明，内质网压力传感器肌醇依赖激酶1 (IRE1α)及其底物转录因子X盒结合蛋白1 (XBP1)驱动器NK细胞对病毒感染和体内肿瘤的反应。IRE1α-XBP1位于哺乳动物雷帕霉素信号通路下游的靶点，对激活的老鼠和人类NK细胞的扩张至关重要。转录组和染色质免疫沉淀分析显示，c-Myc是XBP1调控NK细胞增殖的一个新的直接的下游靶点。基因消融或药物抑制IRE1α下调c-Myc,NK细胞c-Myc单倍体基因不足表型模拟IRE1α-XBP1缺乏。c-Myc超表达很大程度上拯救了增殖缺陷的IRE1α−/−NK细胞。和c-Myc相似,IRE1α-XBP1也促进NK细胞的氧化磷酸化。总的来说,研究证明IRE1α-XBP1-cMyc轴对NK细胞免疫力,宿主抵御感染以及癌症至关重要。

据了解，自然杀伤免疫细胞是宿主对病原体免疫的重要组成部份。

附：英文原文

Title: The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc

Author: Han Dong, Nicholas M. Adams, Yichi Xu, Jin Cao, David S. J. Allan, James R. Carlyle, Xi Chen, Joseph C. Sun, Laurie H. Glimcher

Issue&Volume:Volume 20 Issue 7, July 2019

Abstract: Natural killer (NK) cells are critical mediators of host immunity to pathogens. Here, we demonstrate that the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1α) and its substrate transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1α-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mammalian target of rapamycin signaling pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1α downregulated c-Myc, and NK cells with c-Myc haploinsufficency phenocopied IRE1α-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1α−/− NK cells. Like c-Myc, IRE1α-XBP1 also promotes oxidative phosphorylation in NK cells. Overall, our study identifies a IRE1α-XBP1-cMyc axis in NK cell immunity, providing insight into host protection against infection and cancer.

DOI: 10.1038/s41590-019-0388-z

Source: https://www.nature.com/articles/s41590-019-0388-z