Keller Kate E, Wirtz Mary K
Casey Eye Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Casey Eye Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Exp Eye Res. 2017 May;158:154-160. doi: 10.1016/j.exer.2016.06.003. Epub 2016 Jun 11.
Evidence is accumulating to suggest that mutations in the Ankyrin and SOCS Box-containing protein-10 (ASB10) gene are associated with glaucoma. Since its identification in a large Oregon family with primary open-angle glaucoma (POAG), ASB10 variants have been associated with disease in US, German and Pakistani cohorts. ASB10 is a member of the ASB family of proteins, which have a common structure including a unique N-terminus, a variable number of central ankyrin (ANK) repeat domains and a suppressor of cytokine signaling (SOCS) box at the C-terminus. Mutations in ASB10 are distributed throughout the entire length of the gene including the two alternatively spliced variants of exon 1. A homozygous mutation in a Pakistani individual with POAG, which lies in the center of the SOCS box, is associated with a particularly severe form of the disease. Like other SOCS box-containing proteins, ASB10 functions in ubiquitin-mediated degradation pathways. The ANK repeats bind to proteins destined for degradation. The SOCS box recruits ubiquitin ligase proteins to form a complex to transfer ubiquitin to a substrate bound to the ANK repeats. The ubiquitin-tagged protein then enters either the proteasomal degradation pathway or the autophagic-lysosomal pathway. The choice of pathway appears to be dependent on which lysine residues are used to build polyubiquitin chains. However, these reciprocal pathways work in tandem to degrade proteins because inhibition of one pathway increases degradation via the other pathway. In this publication, we will review the literature that supports identification of ASB10 as a glaucoma-associated gene and the current knowledge of the function of the ASB10 protein. In addition, we present new data that indicates ASB10 expression is up-regulated by the inflammatory cytokines tumor necrosis factor-α and interleukin-1α. Finally, we will describe the emerging role of other SOCS box-containing proteins in protein degradation pathways in ocular cells.
越来越多的证据表明,锚蛋白和含SOCS盒蛋白10(ASB10)基因的突变与青光眼有关。自从在俄勒冈州一个患有原发性开角型青光眼(POAG)的大家族中被鉴定出来后,ASB10变体已在美国、德国和巴基斯坦的队列研究中与该疾病相关联。ASB10是ASB蛋白家族的成员之一,该家族蛋白具有共同的结构,包括独特的N端、数量可变的中央锚蛋白(ANK)重复结构域以及C端的细胞因子信号抑制(SOCS)盒。ASB10中的突变分布在整个基因长度上,包括外显子1的两种可变剪接变体。一名患有POAG的巴基斯坦个体中位于SOCS盒中心的纯合突变与一种特别严重的疾病形式相关。与其他含SOCS盒的蛋白一样,ASB10在泛素介导的降解途径中发挥作用。ANK重复序列与注定要被降解的蛋白质结合。SOCS盒招募泛素连接酶蛋白形成复合物,将泛素转移到与ANK重复序列结合的底物上。然后,带有泛素标签的蛋白质进入蛋白酶体降解途径或自噬溶酶体途径。途径的选择似乎取决于用于构建多聚泛素链的赖氨酸残基。然而,这些相互的途径协同作用以降解蛋白质,因为抑制一条途径会增加通过另一条途径的降解。在本出版物中,我们将回顾支持将ASB10鉴定为青光眼相关基因的文献以及关于ASB10蛋白功能的当前知识。此外,我们展示了新的数据,表明ASB10的表达受到炎性细胞因子肿瘤坏死因子-α和白细胞介素-1α的上调。最后,我们将描述其他含SOCS盒蛋白在眼细胞蛋白质降解途径中正在出现的作用。