Ubiquitin-independent proteosomal degradation of myelin basic protein contributes to development of neurodegenerative autoimmunity.
Ubiquitin-independent proteosomal degradation of myelin basic protein contributes to development of neurodegenerative autoimmunity.
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髓磷脂碱性蛋白的不依赖于泛素的蛋白酶体降解有助于神经退行性自身免疫的发展。
DOI：
10.1096/fj.14-259333
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Gabibov A
中科院分区：
文献类型：
--
作者：
Belogurov A Jr;Kuzina E;Kudriaeva A;Kononikhin A;Kovalchuk S;Surina Y;Smirnov I;Lomakin Y;Bacheva A;Stepanov A;Karpova Y;Lyupina Y;Kharybin O;Melamed D;Ponomarenko N;Sharova N;Nikolaev E;Gabibov A
最近的发现表明，泛素-蛋白酶体系统参与了癌症、自身免疫和一些神经退行性疾病的发病机制，因此是新的治疗方法的靶点。与蛋白质异常降解有关的一种疾病是多发性硬化症，这是一种自身免疫性疾病，涉及髓鞘自身抗原的处理和呈现，导致轴突破坏。在这里，我们展示了来自实验性自身免疫性脑脊髓炎(EAE)小鼠的脑源性蛋白酶体以泛素不依赖的方式产生显著增加的髓鞘碱性蛋白多肽，诱导细胞毒性淋巴细胞体外靶向成熟的少突胶质细胞。EAE-SJL小鼠脑蛋白酶体对免疫原肽的释放增加了10倍，这是由于EAE-SJL小鼠中枢神经系统中组成蛋白酶体和β高免疫蛋白酶体之间的平衡发生了剧烈的变化。我们发现，在EAE期间，驻留的中枢神经系统细胞中的β1i增加，而β5i是通过血脑屏障渗入的淋巴细胞输入的。在体外，肽基环氧酮特异性地抑制脑源性β-I高免疫蛋白酶体(KOBS/[I]=240M-−-1S-−-1)，在体内，其剂量为0.5 mg/kg时，可改善正在进行的EAE。因此，我们的发现为病理生理条件下的髓鞘代谢提供了新的见解，并揭示了免疫蛋白酶体的β1i亚单位是治疗自身免疫性神经疾病的潜在目标。--小Belogurov，A.，Kuzina，E.，Kudriaeva，A.，Kononikhin，A.，Kovalchuk，S.，Surina，Y.，Smirnov，I.，Lomakin，Y.，Bacheva，A.，Stepanov，A.，Karpova，Y.，Lyupina，Y.，Kharybin，O.，Melame，D.，Ponomarenko，N.，Sharova，N.，Nikolaev，E.，Gabibov，O.髓鞘碱性蛋白的泛素非依赖性蛋白酶体降解有助于神经退行性自身免疫的发展。
Recent findings indicate that the ubiquitin–proteasome system is involved in the pathogenesis of cancer as well as autoimmune and several neurodegenerative diseases, and is thus a target for novel therapeutics. One disease that is related to aberrant protein degradation is multiple sclerosis, an autoimmune disorder involving the processing and presentation of myelin autoantigens that leads to the destruction of axons. Here, we show that brain-derived proteasomes from SJL mice with experimental autoimmune encephalomyelitis (EAE) in an ubiquitin-independent manner generate significantly increased amounts of myelin basic protein peptides that induces cytotoxic lymphocytes to target mature oligodendrocytes ex vivo. Ten times enhanced release of immunogenic peptides by cerebral proteasomes from EAE-SJL mice is caused by a dramatic shift in the balance between constitutive and β1ihigh immunoproteasomes in the CNS of SJL mice with EAE. We found that during EAE, β1i is increased in resident CNS cells, whereas β5i is imported by infiltrating lymphocytes through the blood–brain barrier. Peptidyl epoxyketone specifically inhibits brain-derived β1ihigh immunoproteasomes in vitro (kobs/[I] = 240 M−1s−1), and at a dose of 0.5 mg/kg, it ameliorates ongoing EAE in vivo. Therefore, our findings provide novel insights into myelin metabolism in pathophysiologic conditions and reveal that the β1i subunit of the immunoproteasome is a potential target to treat autoimmune neurologic diseases.—Belogurov Jr., A., Kuzina, E., Kudriaeva, A., Kononikhin, A., Kovalchuk, S., Surina, Y., Smirnov, I., Lomakin, Y., Bacheva, A., Stepanov, A., Karpova, Y., Lyupina, Y., Kharybin, O., Melamed, D., Ponomarenko, N., Sharova, N., Nikolaev, E., Gabibov, A. Ubiquitin-independent proteosomal degradation of myelin basic protein contributes to development of neurodegenerative autoimmunity.
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影响因子：
3.7
作者：
Mishto M;Bellavista E;Ligorio C;Textoris-Taube K;Santoro A;Giordano M;D'Alfonso S;Listì F;Nacmias B;Cellini E;Leone M;Grimaldi LM;Fenoglio C;Esposito F;Martinelli-Boneschi F;Galimberti D;Scarpini E;Seifert U;Amato MP;Caruso C;Foschini MP;Kloetzel PM;Franceschi C
通讯作者：
Franceschi C
影响因子：
4.4
作者：
Basler, Michael;Lauer, Christoph;Groettrup, Marcus
通讯作者：
Groettrup, Marcus
影响因子：
3.3
作者：
Frausto, Ricardo F.;Crocker, Stephen J.;Whitton, J. Lindsay
通讯作者：
Whitton, J. Lindsay
DOI：
10.1073/pnas.78.2.761
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
CIECHANOVER, A;HELLER, H;HERSHKO, A
通讯作者：
HERSHKO, A
影响因子：
100.3
作者：
Groettrup, Marcus;Kirk, Christopher J.;Basler, Michael
通讯作者：
Basler, Michael