Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Nat Immunol. 2013 Jan;14(1):27-33. doi: 10.1038/ni.2478. Epub 2012 Nov 25.
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.
E3 连接酶 ARIH2 具有独特的结构和延伸泛素链的机制。为了了解其生理作用，我们生成了基因靶向敲除 ARIH2 的小鼠。ARIH2 缺陷导致 C57BL/6 小鼠胚胎死亡。在混合遗传背景下，致死性减弱，一些小鼠在断奶后存活下来，但随后会死于侵袭性多器官炎症反应。我们发现，在树突状细胞（DCs）中，ARIH2 导致核内抑制剂 IκBβ 的降解，从而使其无法在核内隔离、保护和转录共激活转录因子亚基 p65。ARIH2 的缺失导致 DC 中转录因子 NF-κB 的失调激活，这导致用缺乏 ARIH2 的造血干细胞重建的 ARIH2 充足小鼠的免疫系统致命激活。我们的数据为靶向 ARIH2 功能提供了治疗意义。
