Decreased levels of constitutive proteasomes in experimental autoimmune encephalomyelitis may be caused by a combination of subunit displacement and reduced Nfe2l1 expression.
Decreased levels of constitutive proteasomes in experimental autoimmune encephalomyelitis may be caused by a combination of subunit displacement and reduced Nfe2l1 expression.
复制标题
实验性自身免疫性脑脊髓炎中组成型蛋白酶体水平降低可能是由亚基移位和 Nfe2l1 表达减少共同引起的。
DOI：
10.1111/jnc.14912
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发表时间：
2020
影响因子：
4.7
通讯作者：
Bizzozero,OscarA
中科院分区：
文献类型：
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作者：
Shanley,KaraL;Hu,Che-Lin;Bizzozero,OscarA
本研究的目的是确定蛋白酶体生物合成中的亚基置换和/或改变是否可以解释实验性自身免疫性脑脊髓炎（EAE）小鼠脊髓中组成性蛋白酶体（c-20 S）和免疫蛋白酶体（i-20 S）水平的变化。为此，通过用MOG 35 - 55肽免疫在C57 BL/6小鼠中诱导EAE。在疾病过程中的不同时间收集脊髓，并用于蛋白质印迹，RNA分析和免疫组织化学。结果表明，随着i-20 S和激活剂PA 28在EAE中表达的增加，c-20 S在mRNA和蛋白水平上的表达随之下降。这些变化在神经元和星形胶质细胞中观察到，但在少突胶质细胞中没有观察到。EAE中i-20 S-特异性亚基β 5 i和PA 28 α/β的增加量与干扰素-γ及其下游效应物p-信号转导子和转录激活因子1和干扰素调节因子-1的水平相关，但与活化B细胞的核因子κ-轻链-增强子的水平无关。这表明信号转导子和转录激活子1/干扰素调节因子-1途径是唯一负责诱导这些亚基的途径。对应于c-20 S特异性亚基β5的mRNA和蛋白水平的降低也可能是由于核因子（红细胞衍生2）样-1（Nrf 1或Nfe 2l 1），特别是Nrf 1 α和Nrf 1 β的表达降低。低Nfe 2l 1 mRNA表达不太可能是由雷帕霉素信号的哺乳动物靶点减少引起的，但可能是前B细胞白血病同源框1转录因子水平降低的结果。总之，这些发现表明亚基置换和Nrf 1表达减少的组合可能是EAE中c-20 S损伤的原因。目前的工作提供了深入了解蛋白酶体表达的动力学在中枢神经系统的EAE小鼠，是第一个探索Nrf 1信号在炎性脱髓鞘疾病。
The goal of this study was to determine if subunit displacement and/or alterations in proteasome biosynthesis could explain the changes observed in the levels of constitutive proteasomes (c‐20S) and immunoproteasomes (i‐20S) in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE). To this end, EAE was induced in C57BL/6 mice by immunization with MOG35–55peptide. Spinal cords were collected at different times during the disease course and used for western blotting, RNA analysis, and immunohistochemistry. The results show that, as expression of i‐20S and the activator PA28 rise in EAE, there is a concomitant decline in that of c‐20S at the mRNA and protein level. These changes are observed in neurons and astrocytes but not in oligodendrocytes. The increased amounts of the i‐20S‐specific subunit β5i and PA28α/β in EAE correlate with the levels of interferon‐γ and its downstream effectors p‐signal transducer and activator of transcription 1 and interferon regulatory factor‐1, but not with those of nuclear factor kappa‐light‐chain‐enhancer of activated B cells. This suggests that the signal transducer and activator of transcription 1/interferon regulatory factor‐1 pathway is solely responsible for the induction of these subunits. The decrease in the mRNA and protein levels corresponding to the c‐20S‐specific subunit β5 may also be due to reduced expression of the nuclear factor (erythroid‐derived 2)‐like‐1 (Nrf1 orNfe2l1), specifically Nrf1α and Nrf1β. LowNfe2l1mRNA expression is unlikely caused by reduced mammalian target of rapamycin signaling but could be the result of diminished pre‐B‐cell leukemia homeobox‐1 transcription factor levels. Together, these findings suggest that a combination of subunit displacement and reduced Nrf1 expression may be responsible for c‐20S impairment in EAE. The present work provides insights into the dynamics of proteasome expression in the CNS of EAE mice and is the first to explore Nrf1 signaling in an inflammatory demyelinating disorder.