Protein disulphide isomerase is required for signal peptide peptidase-mediated protein degradation
Protein disulphide isomerase is required for signal peptide peptidase-mediated protein degradation
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DOI：
10.1038/emboj.2009.359
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发表时间：
2010-01-20
期刊：
影响因子：
11.4
通讯作者：
Ahn, Kwangseog
中科院分区：
文献类型：
--
作者：
Lee, Seong-Ok;Cho, Kwangmin;Ahn, Kwangseog
人巨细胞病毒糖蛋白US2诱导MHC-I类重链从内质网(ER)错位进入胞浆，并以其为靶点进行蛋白酶体降解。信号肽酶(SPP)在US2诱导的MHC-I类重链错位中起着不可或缺的作用，但其作用机制尚不清楚。在这里，我们表明，通过RNA介导的干扰敲除蛋白质二硫化物异构酶(PDI)可以抑制US2催化的MHC I类分子的降解，但不能抑制其功能同系物US11的降解。PDI底物结合突变体的过表达，而不是催化不活跃的突变体，通过阻止MHC I类分子从US2中释放，显性-负向抑制了US2介导的MHC I类分子的错位。此外，独立于US2的PDI与SPP结合以及PDI的敲除可抑制SPP介导的CD3 Delta的降解，但不能抑制依赖于Derlin-1的CFTR DeltaF508的降解。综上所述，我们的数据表明PDI是SPP介导的ER相关降解机制的一个组成部分。EMBO期刊(2010)29,363-375。DOI：10.1038/Intemj.2009.359；2009年11月26日在线发布
The human cytomegalovirus glycoprotein US2 induces dislocation of MHC class I heavy chains from the endoplasmic reticulum (ER) into the cytosol and targets them for proteasomal degradation. Signal peptide peptidase (SPP) has been shown to be integral for US2-induced dislocation of MHC class I heavy chains although its mechanism of action remains poorly understood. Here, we show that knockdown of protein disulphide isomerase (PDI) by RNA-mediated interference inhibited the degradation of MHC class I molecules catalysed by US2 but not by its functional homolog US11. Overexpression of the substrate-binding mutant of PDI, but not the catalytically inactive mutant, dominant-negatively inhibited US2-mediated dislocation of MHC class I molecules by preventing their release from US2. Furthermore, PDI associated with SPP independently of US2 and knockdown of PDI inhibited SPP-mediated degradation of CD3 delta but not Derlin-1-dependent degradation of CFTR DeltaF508. Together, our data suggest that PDI is a component of the SPP-mediated ER-associated degradation machinery. The EMBO Journal ( 2010) 29, 363-375. doi: 10.1038/emboj.2009.359; Published online 26 November 2009