Endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 1 targets misfolded HLA-B27 dimers for endoplasmic reticulum-associated degradation.
Endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 1 targets misfolded HLA-B27 dimers for endoplasmic reticulum-associated degradation.
复制标题
DOI：
10.1002/art.38809
复制
发表时间：
2014-11
影响因子：
13.3
通讯作者：
Antoniou, Antony N.
中科院分区：
文献类型：
--
作者：
Guiliano, David B.;Fussell, Helen;Lenart, Izabela;Tsao, Edward;Nesbeth, Darren;Fletcher, Adam J.;Campbell, Elaine C.;Yousaf, Nasim;Williams, Sarah;Santos, Susana;Cameron, Amy;Towers, Greg J.;Kellam, Paul;Hebert, Daniel N.;Gould, Keith G.;Powis, Simon J.;Antoniou, Antony N.
HLA-B27形成错误折叠的重链二聚体，可能通过诱导内质网(ER)应激和未折叠蛋白反应(UPR)而易患炎症性关节炎。我们想要确定UPR诱导的ER相关降解(ERAD)通路在处理HLA-B27二聚体构象中的作用。建立了仅表达两个拷贝的末端带有Sv5标记的人类白细胞抗原-B27的HeLa细胞系。用免疫印迹法检测内质网应激诱导的EDEM1蛋白过表达和二聚体水平。EDEM1、UPR相关转录因子XBP-1、E3泛素连接酶Hrd1、降解相关的Derlin 1和2蛋白均被短发夹状RNA或显性负性突变体抑制。用内质网应激诱导药动学和脉冲追踪法证实了HLAB27的UPR相关ERAD。我们证明了UPR诱导的机制可以靶向HLA-B27二聚体，并且二聚体的形成可以通过改变UPR诱导的ERAD途径的组成部分的表达水平来控制。检测到与EDEM1结合的HL A-B27二聚体和错误折叠的MHC I类单体分子，EDEM1过表达抑制了HL A-B27二聚体的形成。EDEM1抑制可导致HLAB27二聚体上调，而UPR诱导的二聚体ERAD在缺乏EDEM1的情况下被阻止。在缺乏XBP-1、Hrd1和derlin1/2的情况下，HLA-B27二聚体的形成也被促进。本文描述的UPR ERAD通路可以处理HLAB27二聚体，为调节HLAB27相关性炎症性疾病提供了一个潜在的新的治疗靶点。
HLA-B27 forms misfolded heavy chain dimers, which may predispose individuals to inflammatory arthritis by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We wanted to define the role of the UPR induced ER associated degradation (ERAD) pathway in the disposal of HLA-B27 dimeric conformers. HeLa cell lines expressing only two copies of a carboxy terminally Sv5 tagged HLA-B27 were generated. The ER stress induced EDEM1 protein was over expressed by transfection and dimer levels monitored by immunoblotting. EDEM1, the UPR associated transcription factor XBP-1, the E3 ubiquitin ligase HRD1, the degradation associated derlin 1 and 2 proteins were inhibited by either short hairpin RNA or dominant negative mutants. The UPR associated ERAD of HLA-B27 was confirmed using ER stress inducing pharamacological agents in kinetic and pulse chase assays. We demonstrate that UPR induced machinery can target HLA-B27 dimers, and that dimer formation can be controlled by alterations to expression levels of components of the UPR induced ERAD pathway. HLA-B27 dimers and misfolded MHC class I monomeric molecules were detected bound to EDEM1, with overexpression of EDEM1 inhibiting HLA-B27 dimer formation. EDEM1 inhibition resulted in upregulation of HLA-B27 dimers, whilst UPR induced ERAD of dimers was prevented in the absence of EDEM1. HLA-B27 dimer formation was also enhanced in the absence of XBP-1, HRD1 and derlin1/2. The UPR ERAD pathway as described here can dispose of HLA-B27 dimers and presents a potential novel therapeutic target for the modulation of HLA-B27 associated inflammatory disease.
登录
查看更多内容
影响因子：
16
作者：
Cormier, James H.;Tamura, Taku;Sunryd, Johan C.;Hebert, Daniel N.
通讯作者：
Hebert, Daniel N.
影响因子：
64.8
作者：
Lilley, BN;Ploegh, HL
通讯作者：
Ploegh, HL
影响因子：
4.8
作者：
Antoniou, AN;Ford, S;Powis, SJ
通讯作者：
Powis, SJ
影响因子：
6.4
作者：
Campbell, Elaine C.;Fettke, Franziska;Powis, Simon J.
通讯作者：
Powis, Simon J.
DOI：
10.1083/jcb.200204122
发表时间：
2002-07-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Molinari M;Galli C;Piccaluga V;Pieren M;Paganetti P
通讯作者：
Paganetti P