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Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease [Genetics]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-04-13 , DOI: 10.1073/pnas.2102804118
Tom Le Voyer, Anna-Lena Neehus, Rui Yang, Masato Ogishi, Jérémie Rosain, Fayhan Alroqi, Maha Alshalan, Sophie Blumental, Fatima Al Ali, Taushif Khan, Manar Ata, Laurence Rozen, Anne Demulder, Paul Bastard, Conor Gruber, Manon Roynard, Yoann Seeleuthener, Franck Rapaport, Benedetta Bigio, Maya Chrabieh, Danielle Sng, Laureline Berteloot, Nathalie Boddaert, Flore Rozenberg, Saleh Al-Muhsen, Aida Bertoli-Avella, Laurent Abel, Dusan Bogunovic, Nico Marr, Davood Mansouri, Fuad Al Mutairi, Vivien Béziat, Dominique Weil, Seyed Alireza Mahdaviani, Alina Ferster, Shen-Ying Zhang, Bruno Reversade, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Jacinta Bustamante

Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette–Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.



中文翻译:

单核细胞增多症和分枝杆菌病患者的应激颗粒ZNFX1遗传性缺乏[遗传学]

由于淋巴样细胞产生的IFN-γ不足,骨髓细胞对这种细胞因子的反应受损或两者兼而有之,人为天生的IFN-γ错误就成为了分枝杆菌疾病的基础。我们报告了来自两个无关亲戚的四名患者,这些患者患有间歇性单核细胞增多症和分枝杆菌病,包括卡介苗-瓜林病和弥漫性结核病,且无已知的先天性IFN-γ错误。这些患者的ZNFX1是纯合子变异(p.S959 *和p.E1606Rfs * 10)预测为功能丧失(pLOF)。在公共数据库中没有pLOF变异的纯合受试者。ZNFX1是一种保守且广泛表达的解旋酶,但其生物学仍未知。人们认为它在小鼠中起病毒双链RNA传感器的作用,但是这些患者没有遭受严重的病毒性疾病。我们分析了在A549和HeLa细胞系中过表达以及在THP1和成纤维细胞系的刺激下其亚细胞定位。我们发现这种细胞质蛋白可以被募集到甚至诱导应激颗粒。p.E1606Rfs * 10变异纯合患者的细胞系中的内源性ZNFX1蛋白被截短,而p.S959 *变异患者的细胞系中的ZNFX1表达被消除。这些患者中的淋巴细胞亚群以正常频率出现,并正常产生IFN-γ。受测患者的造血和非造血细胞对IFN-γ正常反应。我们的结果表明,人ZNFX1与应激颗粒相关,对于单核细胞稳态和对分枝杆菌的保护性免疫都是必不可少的。

更新日期:2021-04-06
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