Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia.
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Curr Rheumatol Rep. 2018 May 30;20(7):39. doi: 10.1007/s11926-018-0749-x.
The nuclear factor κB (NF-κB) pathway is tightly regulated through multiple posttranslational mechanisms including ubiquitination. Mutations in these regulatory pathways can cause disease and are the focus of this review.
The linear ubiquitin chain assembly complex (LUBAC) is a trimer made up of HOIL-1L, SHARPIN, and the catalytic subunit HOIP. Loss of function mutations in HOIL-1L and HOIP result in largely overlapping phenotypes, characterized by multi-organ autoinflammation, immunodeficiency, and amylopectinosis. Interestingly, patient fibroblasts exhibited diminished IL-1β- and TNF-induced NF-κB activation, yet monocytes were hyper-responsive to IL-1β, hinting at cell type or target specific roles of LUBAC-mediated ubiquitination. Ubiquitin-driven signaling is counterbalanced by deubiquitinase enzymes (DUBs), such as OTULIN and A20. Hypomorphic mutations in OTULIN result in elevated NF-κB signaling causing an autoinflammatory syndrome. Similarly, patients with high-penetrance heterozygous mutations in the gene encoding A20 (haploinsufficiency of A20 (HA20)) display excessive ubiquitination and increased activity of NF-κB and of NLRP3 inflammasome activation. HA20 patients present with Behçet-like characteristics or an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype, indicating diverse protein functions. This review summarizes recent discoveries in the field of NF-kB-related autoinflammatory diseases (relopathies) within the past 3 years and points to several questions that still remain unanswered.
核因子 κB（NF-κB）通路通过多种翻译后机制（包括泛素化）进行严密调控。这些调控途径的突变可导致疾病，这也是本综述的重点。
线性泛素链组装复合物（LUBAC）由 HOIL-1L、SHARPIN 和催化亚基 HOIP 组成，三聚体。HOIL-1L 和 HOIP 的功能丧失突变导致表型大部分重叠，其特征为多器官自身炎症、免疫缺陷和淀粉样变性。有趣的是，患者成纤维细胞表现出减弱的 IL-1β 和 TNF 诱导的 NF-κB 激活，而单核细胞对 IL-1β 反应过度，这表明 LUBAC 介导的泛素化具有细胞类型或靶标特异性作用。泛素驱动的信号被去泛素化酶（DUBs）如 OTULIN 和 A20 所平衡。OTULIN 的功能减弱突变导致 NF-κB 信号升高，引起自身炎症综合征。同样，编码 A20 的基因（A20 杂合不足（HA20））存在高外显率杂合突变的患者表现出泛素化增加以及 NF-κB 和 NLRP3 炎性小体激活活性增加。HA20 患者表现出 Behçet 样特征或自身免疫性淋巴增生性综合征（ALPS）样表型，表明其具有不同的蛋白功能。本综述总结了过去 3 年中 NF-κB 相关自身炎症性疾病（relopathies）领域的最新发现，并指出了仍存在的一些未解决的问题。
