Proteasome Composition in Cytokine-Treated Neurons and Astrocytes is Determined Mainly by Subunit Displacement.
Proteasome Composition in Cytokine-Treated Neurons and Astrocytes is Determined Mainly by Subunit Displacement.
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细胞因子处理的神经元和星形胶质细胞中的蛋白酶体组成主要由亚基置换决定。
DOI：
10.1007/s11064-020-02958-8
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发表时间：
2020
影响因子：
4.4
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
在这项研究中，我们研究了亚基置换和/或蛋白酶体生物合成的改变是否是与细胞因子混合物（IFN-γ/TNF-α/IL-1β）培养的神经元和星形胶质细胞中组成性蛋白酶体（c-20 S）、免疫蛋白酶体（i-20 S）和激活剂PA 28和PA 700水平变化有关。将两种细胞类型暴露于细胞因子24 h可增加i-20 S特异性亚基β 5 i和PA 28 α/β的mRNA和蛋白表达，并导致c-20 S特异性亚基β5的量下降。由于β5 mRNA水平未受细胞因子处理的影响，因此可以得出结论，组成性β亚基被诱导性β5i亚基置换可能是c-20 S降低的潜在机制。正如预期的那样，IFN-γ诱导亚基的量的增加与磷酸化STAT-1和干扰素调节因子-1（IRF-1）的表达升高相一致。然而，抑制经苦参碱处理的星形胶质细胞中的NF-κB信号传导可降低IRF-1的表达，而不影响i-20 S、c-20 S和PA 28的表达。这表明STAT-1本身能够增加i20 S特异性亚基和PA 28 α/β的转录。蛋白酶体β5 mRNA表达没有减少与Nrf 1（Nfe 2l 1）和Nrf 2（Nfe 2l 2）水平没有被促炎细胞因子降低的事实一致。与此相反，我们以前发现，有一个显着的Nrf 1失调和β5 mRNA表达减少，在脊髓中的实验性自身免疫性脑脊髓炎（EAE）小鼠。因此，除了促炎环境之外，在EAE中存在不存在于马槟榔碱处理的细胞中的应激源。
In this study, we investigated if subunit displacement and/or alterations in proteasome biosynthesis are responsible for the changes in the levels of constitutive proteasomes (c-20S), immunoproteasomes (i-20S) and the activators PA28 and PA700 in neurons and astrocytes cultured with a cytokine mixture (IFN-γ/TNF-α/IL-1β). Exposure of both cell types to cytokines for 24 h increases mRNA and protein expression of the i-20S-specific subunit β5i and PA28α/β, and leads to a decline in the amount of the c-20S-specific subunit β5. Since β5 mRNA levels are unchanged by the cytokine treatment, it is fair to conclude that displacement of constitutive β-subunits with inducible β5i subunits is likely the mechanism underlying the decrease in c-20S. As expected, the increase in the amount of the IFN-γ-inducible subunits coincides with elevated expression of phospho-STAT-1 and interferon regulatory factor-1 (IRF-1). However, inhibition of NF-κB signaling in cytokine-treated astrocytes reduces IRF-1 expression without affecting that of i-20S, c-20S and PA28. This suggests that STAT-1 is capable of increasing the transcription of i20S-specific subunits and PA28α/β by itself. The lack of a decrease in proteasome β5 mRNA expression is consistent with the fact that Nrf1 (Nfe2l1) and Nrf2 (Nfe2l2) levels are not reduced by pro-inflammatory cytokines. In contrast, we previously found that there is a significant Nrf1 dysregulation and reduced β5 mRNA expression in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE). Thus, there are stressors in EAE, other than a pro-inflammatory environment, that are not present in cytokine-treated cells.