GILT expression in B cells diminishes cathepsin S steady-state protein expression and activity.
GILT expression in B cells diminishes cathepsin S steady-state protein expression and activity.
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DOI：
10.1002/eji.201242379
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发表时间：
2013-01
影响因子：
5.4
通讯作者：
Hastings, Karen Taraszka
中科院分区：
文献类型：
--
作者：
Phipps-Yonas, Hannah;Semik, Vikki;Hastings, Karen Taraszka
关键词：
MHC II类限制性Ag加工需要内吞途径中的蛋白降解以活化CD 4 + T细胞。γ-干扰素诱导型溶酶体巯基还原酶（GILT）通过还原该区室中的蛋白质二硫键促进Ag加工。溶酶体半胱氨酸蛋白酶组织蛋白酶S（CatS）含有二硫键，介导MHC II类限制性加工的重要步骤，包括大多肽的蛋白质水解和不变链的切割。我们试图确定GILT的还原酶活性是否调节CatS的表达和功能。共聚焦显微镜证实GILT和CatS共定位于B细胞的溶酶体内。GILT表达转录后降低了原代B细胞和B细胞系中CatS的稳态蛋白表达。GILT基本上不改变其他溶酶体蛋白的表达，包括H2-M、H2-O或CatL。GILT的还原酶活性位点是减少CatS蛋白水平所必需的，GILT表达降低了CatS的半衰期，表明GILT介导的蛋白质二硫键还原增强了CatS降解。GILT表达降低了CatS选择性底物的蛋白水解。这项研究说明了一种生理机制，调节CatS和微调MHC II类限制性Ag加工和CatS抑制剂的发展，这是正在调查的治疗自身免疫性疾病的影响。
MHC class II-restricted Ag processing requires protein degradation in the endocytic pathway for the activation of CD4+ T cells. Gamma-interferon-inducible lysosomal thiol reductase (GILT) facilitates Ag processing by reducing protein disulfide bonds in this compartment. Lysosomal cysteine protease cathepsin S (CatS) contains disulfide bonds and mediates essential steps in MHC class II-restricted processing, including proteolysis of large polypeptides and cleavage of the invariant chain. We sought to determine whether GILT’s reductase activity regulates CatS expression and function. Confocal microscopy confirmed that GILT and CatS colocalized within lysosomes of B cells. GILT expression posttranscriptionally decreased the steady-state protein expression of CatS in primary B cells and B-cell lines. GILT did not substantially alter the expression of other lysosomal proteins, including H2-M, H2-O, or CatL. GILT’s reductase active site was necessary for diminished CatS protein levels, and GILT expression decreased the half-life of CatS, suggesting that GILT-mediated reduction of protein disulfide bonds enhances CatS degradation. GILT expression decreased the proteolysis of a CatS selective substrate. This study illustrates a physiologic mechanism that regulates CatS and has implications for fine tuning MHC class II-restricted Ag processing and for the development of CatS inhibitors, which are under investigation for the treatment of autoimmune disease.
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影响因子：
56.9
作者：
Nakagawa, T;Roth, W;Rudensky, AY
通讯作者：
Rudensky, AY
DOI：
10.1073/pnas.97.2.745
发表时间：
2000-01-18
影响因子：
11.1
作者：
Arunachalam, B;Phan, UT;Cresswell, P
通讯作者：
Cresswell, P
影响因子：
4.4
作者：
Hastings, K. Taraszka;Lackman, Rebecca L.;Cresswell, Peter
通讯作者：
Cresswell, Peter
影响因子：
5.8
作者：
Goldstein, Oliver G.;Hajiaghamohseni, Laela M.;Haque, Azizul
通讯作者：
Haque, Azizul
影响因子：
64.5
作者：
BAKKE, O;DOBBERSTEIN, B
通讯作者：
DOBBERSTEIN, B