nature-immunology201301-1

ARIH2是一种环指相扣型E3连接酶。来自的墨尔本大学的Pellegrini及其同事发现ARIH2是树突细胞中用于限制过多NF-κB信号传递的蛋白因子。机体缺失ARIH2会导致由过度的炎症反应引起的胚胎死亡。相关的研究论文于2012年11月25日在线发表在《Nature Immunology》杂志上。

-2013年1月《自然-免疫》

中文翻译


【题目】ARIH2是胚胎发生所需蛋白质

【译文】E3连接酶ARIH2具有不同的结构和泛素链延伸机制。为了理解它的生理功能,本研究获得了ARIH2编码基因缺陷小鼠。ARIH2缺陷导致C57BL/6小鼠在胚胎期就死亡。在混合遗传背景下,突变体小鼠的死亡率降低,有一些小鼠还存活到断奶期,然后死于侵袭性的多器官炎症反应。本研究发现树突细胞(DCs)中的ARIH2会引起核内抑制剂IκBβ降解,这导致ARIH2不能隔离、保护和转录共激活核内的转录因子亚基p65。树突细胞缺失ARIH2会引起转录因子NF-κB的异常激活,这导致致命性免疫系统的激活,在ARIH2小鼠中重建ARIH2缺陷的造血干细胞。这项研究表明以ARIH2作为药物靶标,开发出相应的药物,对于治疗免疫系统疾病具有一定的意义。

英文原稿


 

[Title]: ARIH2 is essential for embryogenesis, and its hematopoietic deficiency causes lethal activation of the immune system 

[Authors]:Amy E Lin, Gregor Ebert, Yongkai Ow, Simon P Preston, Jesse G Toe, James P Cooney, Hamish W Scott, Masato Sasaki, Samuel D Saibil, Dilan Dissanayake, Raymond H Kim, Andrew Wakeham, Annick You-Ten, Arda Shahinian, Gordon Duncan, Jennifer Silvester, Pamela S Ohashi, Tak W Mak & Marc Pellegrini

[Abstract]: The E3 ligase ARIH2 has an unusual structure and mechanism of elongating ubiquitin chains. To understand its physiological role, we generated gene-targeted mice deficient in ARIH2. ARIH2 deficiency resulted in the embryonic death of C57BL/6 mice. On a mixed genetic background, the lethality was attenuated, with some mice surviving beyond weaning and then succumbing to an aggressive multiorgan inflammatory response. We found that in dendritic cells (DCs), ARIH2 caused degradation of the inhibitor IκBβ in the nucleus, which abrogated its ability to sequester, protect and transcriptionally coactivate the transcription factor subunit p65 in the nucleus. Loss of ARIH2 caused dysregulated activation of the transcription factor NF-κB in DCs, which led to lethal activation of the immune system in ARIH2-sufficent mice reconstituted with ARIH2-deficient hematopoietic stem cells. Our data have therapeutic implications for targeting ARIH2 function.

原文地址

http://www.nature.com/ni/journal/v14/n1/abs/ni.2478.html

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