ISGylation is induced in neurons by demyelination driving ISG15-dependent microglial activation.
ISGylation is induced in neurons by demyelination driving ISG15-dependent microglial activation.
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DOI：
10.1186/s12974-022-02618-4
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发表时间：
2022-10-20
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
多发性硬化症中灰质病理学和弥漫性神经元损伤的原因仍不完全清楚。白质病变产生的轴突应激信号被认为在引发这种弥漫性灰质病理学中发挥作用。因此，为了确定脱髓鞘轴突产生的神经元中最上游的转录反应，我们分析了脱髓鞘疾病小鼠模型中主动翻译神经元转录物的转录组。在最上调的基因中，我们鉴定了与 ISGylation 途径相关的转录本。 ISGylation 是指类泛素分子干扰素刺激基因 (ISG) 15 与 E1 ISG15 激活酶、E2 ISG15 缀合酶和 E3 ISG15 蛋白连接酶靶向的底物上的赖氨酸残基共价连接。我们进一步证实，ISG15 表达在 MS 皮质和深层灰质中增加。在研究神经元 ISG15 上调的功能影响时，我们注意到 ISG15 表达与神经元细胞外囊泡蛋白和 miRNA 货物的变化相关。具体来说，细胞外囊泡相关的 miRNA 倾向于促炎和神经毒性 miRNA 的频率增加，而抗炎和神经保护 miRNA 的频率降低。此外，我们发现ISG15以CD11b依赖性方式直接激活小胶质细胞，并且通过表达ISG15的神经元的EV处理可增强小胶质细胞的激活。有必要进一步研究 ISG15 和 ISGylation 在 MS 和神经退行性疾病神经元中的作用。在线版本包含可在 10.1186/s12974-022-02618-4 获取的补充材料。
The causes of grey matter pathology and diffuse neuron injury in MS remain incompletely understood. Axonal stress signals arising from white matter lesions has been suggested to play a role in initiating this diffuse grey matter pathology. Therefore, to identify the most upstream transcriptional responses in neurons arising from demyelinated axons, we analyzed the transcriptome of actively translating neuronal transcripts in mouse models of demyelinating disease. Among the most upregulated genes, we identified transcripts associated with the ISGylation pathway. ISGylation refers to the covalent attachment of the ubiquitin-like molecule interferon stimulated gene (ISG) 15 to lysine residues on substrates targeted by E1 ISG15-activating enzyme, E2 ISG15-conjugating enzymes and E3 ISG15-protein ligases. We further confirmed that ISG15 expression is increased in MS cortical and deep gray matter. Upon investigating the functional impact of neuronal ISG15 upregulation, we noted that ISG15 expression was associated changes in neuronal extracellular vesicle protein and miRNA cargo. Specifically, extracellular vesicle-associated miRNAs were skewed toward increased frequency of proinflammatory and neurotoxic miRNAs and decreased frequency of anti-inflammatory and neuroprotective miRNAs. Furthermore, we found that ISG15 directly activated microglia in a CD11b-dependent manner and that microglial activation was potentiated by treatment with EVs from neurons expressing ISG15. Further study of the role of ISG15 and ISGylation in neurons in MS and neurodegenerative diseases is warranted. The online version contains supplementary material available at 10.1186/s12974-022-02618-4.
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DOI：
10.1111/febs.13944
发表时间：
2016-12
期刊：
The FEBS journal
影响因子：
--
作者：
Annis RP;Swahari V;Nakamura A;Xie AX;Hammond SM;Deshmukh M
通讯作者：
Deshmukh M
影响因子：
11
作者：
Chopra N;Wang R;Maloney B;Nho K;Beck JS;Pourshafie N;Niculescu A;Saykin AJ;Rinaldi C;Counts SE;Lahiri DK
通讯作者：
Lahiri DK
DOI：
10.1126/science.1224026
发表时间：
2012-09-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bogunovic D;Byun M;Durfee LA;Abhyankar A;Sanal O;Mansouri D;Salem S;Radovanovic I;Grant AV;Adimi P;Mansouri N;Okada S;Bryant VL;Kong XF;Kreins A;Velez MM;Boisson B;Khalilzadeh S;Ozcelik U;Darazam IA;Schoggins JW;Rice CM;Al-Muhsen S;Behr M;Vogt G;Puel A;Bustamante J;Gros P;Huibregtse JM;Abel L;Boisson-Dupuis S;Casanova JL
通讯作者：
Casanova JL
影响因子：
5.3
作者：
Baghi, Masoud;Delavar, Mahsa Rostamian;Ghaedi, Kamran
通讯作者：
Ghaedi, Kamran
CX3CL1/CX3CR1轴通过促进蛛网膜下腔出血后外泌体microRNA-124从神经元向小胶质细胞的递送来减轻早期脑损伤
影响因子：
9.3
作者：
Chen, Xiao;Jiang, Ming;Chen, Gang
通讯作者：
Chen, Gang