我们对人线性泛素化链组装复合物(LUBAC)的了解知之甚少。来自美国纽约洛克菲勒大学的Casanova及其同事鉴定到人LUBAC中的组分的自然突变,借此在体内和体外情况下剖析它的功能。相关的研究论文于10月28日在线发表在《Nature Immunology》期刊上。

-2012年12月《自然-免疫》

中文翻译


【题目】人类免疫缺陷病、自发炎症和支链淀粉病伴随有遗传性的HOIL-1和LUBAC缺陷

【译文】我们发现了一种新型致命的人类遗传性疾病的临床症状和分子解剖特征,这种疾病的特点表现为慢性的自发炎症、侵袭性的细菌感染和肌肉支链淀粉病。来自两个家族的病人带有基因HOIL1RBCK1)双等位基因表达丧失性和功能丧失性突变,其中基因HOIL1编码的蛋白质是线性泛素化链组装复合物(LUBAC)的组分。这些突变导致LUBAC的稳定性受损。在病人纤维母细胞中,响应白细胞介素1β(IL-1β)的NF-κB激活作用发生妥协。相比之下,病人的单核白细胞,特别是单核细胞,对IL-1β高度敏感。人HOIL-1和LUBAC的缺陷的后果是导致细胞对IL-1β响应存在显著差异,不同类型的细胞具有不同的响应特点,这与这些病人特异性的患有自发炎症和免疫缺陷的症状相一致。这些数据表明,在不同类型的细胞中,LUBAC调控NF-κB依赖的IL-1β响应特点也不同。

英文原稿


[Title]: Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency 

[Authors]:: Bertrand Boisson, Emmanuel Laplantine, Carolina Prando, Silvia Giliani, Elisabeth Israelsson, Zhaohui Xu, Avinash Abhyankar, Laura Israël, Giraldina Trevejo-Nunez, Dusan Bogunovic, Alma-Martina Cepika, Donna MacDuff, Maya Chrabieh, Marjorie Hubeau, Fanny Bajolle, Marianne Debré, Evelina Mazzolari, Donatella Vairo, Fabrice Agou, Herbert W Virgin, Xavier Bossuyt, Caroline Rambaud, Fabio Facchetti, Damien Bonnet, Pierre Quartier, Jean-Christophe Fournet, Virginia Pascual, Damien Chaussabel, Luigi D Notarangelo, Anne Puel, Alain Israël, Jean-Laurent Casanova & Capucine Picard

[Abstract]: We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin 1β (IL-1β) was compromised in the patients’ fibroblasts. By contrast, the patients’ mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB–dependent IL-1β responses differently in different cell types.

原文地址

http://www.nature.com/ni/journal/v13/n12/full/ni.2457.html

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