Vetters Jessica, van Helden Mary, De Nolf Clint, Rennen Sofie, Cloots Eva, Van De Velde Evelien, Fayazpour Farzaneh, Van Moorleghem Justine, Vanheerswynghels Manon, Vergote Karl, Boon Louis, Vivier Eric, Lambrecht Bart N, Janssens Sophie
Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium.
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
iScience. 2023 Nov 23;26(12):108570. doi: 10.1016/j.isci.2023.108570. eCollection 2023 Dec 15.
The unfolded protein response (UPR) aims to restore ER homeostasis under conditions of high protein folding load, a function primarily serving secretory cells. Additional, non-canonical UPR functions have recently been unraveled in immune cells. We addressed the function of the inositol-requiring enzyme 1 (IRE1) signaling branch of the UPR in NK cells in homeostasis and microbial challenge. Cell-intrinsic compound deficiency of IRE1 and its downstream transcription factor XBP1 in NKp46 NK cells, did not affect basal NK cell homeostasis, or overall outcome of viral MCMV infection. However, mixed bone marrow chimeras revealed a competitive advantage in the proliferation of IRE1-sufficient Ly49H NK cells after viral infection. CITE-Seq analysis confirmed strong induction of IRE1 early upon infection, concomitant with the activation of a canonical UPR signature. Therefore, we conclude that IRE1/XBP1 activation is required during vigorous NK cell proliferation early upon viral infection, as part of a canonical UPR response.
未折叠蛋白反应（UPR）旨在在高蛋白折叠负荷条件下恢复内质网稳态，这一功能主要服务于分泌细胞。最近，在免疫细胞中发现了额外的非经典UPR功能。我们研究了UPR的肌醇需求酶1（IRE1）信号分支在NK细胞稳态和微生物攻击中的功能。NKp46 NK细胞中IRE1及其下游转录因子XBP1的细胞内源性复合缺陷，不影响基础NK细胞稳态或病毒MCMV感染的总体结果。然而，混合骨髓嵌合体显示，病毒感染后，具有IRE1的Ly49H NK细胞在增殖方面具有竞争优势。CITE-Seq分析证实，感染后早期IRE1强烈诱导，同时激活经典的UPR特征。因此，我们得出结论，在病毒感染早期NK细胞强烈增殖期间，IRE1/XBP1激活是必需的，这是经典UPR反应的一部分。
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