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组蛋白前体mRNA加工失调导致cGAS诱导产生I型干扰素
作者:小柯机器人 发布时间:2020/11/25 16:29:48

英国爱丁堡大学Yanick J. Crow研究小组发现,组蛋白前体mRNA先天加工失调导致cGAS诱导产生I型干扰素。相关论文发表在2020年11月23日出版的《自然-遗传学》杂志上。

在遗传特征未知的I型干扰素病Aicardi–Goutières综合症患者中,研究人员鉴定到LSM11和RNU7-1中存在双等位基因突变,它们编码复制依赖性组蛋白前体mRNA加工复合体的组分。突变与典型组蛋白转录本的加工不当和接头组蛋白化学计量干扰有关。

此外,研究人员还观察到患者来源的成纤维细胞中环鸟苷酸-腺苷酸合成酶(cGAS)的分布发生了变化,并且cGAS-干扰素基因(STING)途径中干扰素信号的增强。最后,研究人员确定了不含接头组蛋白的染色质在体外可更有效地刺激环鸟苷单磷酸-腺苷单磷酸(cGAMP)的产生。最后,研究人员总结核组蛋白作为染色质的关键成分,对于抑制自身DNA的免疫原性至关重要。

据介绍,不适刺激或I型干扰素反应负调控紊乱可能导致自体炎症。

附:英文原文

Title: cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

Author: Carolina Uggenti, Alice Lepelley, Marine Depp, Andrew P. Badrock, Mathieu P. Rodero, Marie-Thrse El-Daher, Gillian I. Rice, Somdutta Dhir, Ann P. Wheeler, Ashish Dhir, Waad Albawardi, Marie-Louise Frmond, Luis Seabra, Jennifer Doig, Natalie Blair, Maria Jos Martin-Niclos, Erika Della Mina, Alejandro Rubio-Roldn, Jose L. Garca-Prez, Duncan Sproul, Jan Rehwinkel, Jonny Hertzog, Anne Boland-Auge, Robert Olaso, Jean-Franois Deleuze, Julien Baruteau, Karine Brochard, Jonathan Buckley, Vanessa Cavallera, Cristina Cereda, Liesbeth M. H. De Waele, Angus Dobbie, Diane Doummar, Frances Elmslie, Margarete Koch-Hogrebe, Ram Kumar, Kate Lamb, John H. Livingston, Anirban Majumdar, Charles Marques Loreno, Simona Orcesi, Sylviane Peudenier, Kevin Rostasy, Caroline A. Salmon, Christiaan Scott, Davide Tonduti, Guy Touati, Marialuisa Valente, Hlio van der Linden, Hilde Van Esch, Marie Vermelle, Kate Webb, Andrew P. Jackson, Martin A. M. Reijns, Nick Gilbert, Yanick J. Crow

Issue&Volume: 2020-11-23

Abstract: Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi–Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA–processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS–stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.

DOI: 10.1038/s41588-020-00737-3

Source: https://www.nature.com/articles/s41588-020-00737-3

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex