Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKKα stability via selective autophagy.
Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKKα stability via selective autophagy.
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膜联蛋白 A1 SUMOylation 通过选择性自噬调节 IKKα 稳定性来调节脑缺血后的小胶质细胞极化
DOI：
10.1126/sciadv.abc5539
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发表时间：
2021-01
期刊：
影响因子：
13.6
通讯作者：
Shi J
中科院分区：
文献类型：
--
作者：
Li X;Xia Q;Mao M;Zhou H;Zheng L;Wang Y;Zeng Z;Yan L;Zhao Y;Shi J
膜联蛋白A1的苏莫化促进抗炎小胶质细胞表型，保护脑缺血损伤。膜联蛋白-A1(ANXA1)最近被认为在脑缺血后的小胶质细胞激活中发挥作用，但其潜在的机制仍不清楚。在这里，我们证明了ANXA1是通过SUMO化修饰的，并且SUMO化的ANXA1可以促进小胶质细胞的有益表型极化。在机制上，Sumoylated ANXA1抑制核因子κB的激活和促炎介质的产生。进一步的研究表明，Sumoylated ANXA1靶向IκB激酶(IKK)复合体，选择性地促进IKKα的降解。同时，我们检测到Sumoylated ANXA1通过选择性自噬促进了IKKα和NBR1间的相互作用，从而促进了IKKα的降解。进一步的研究表明，在小胶质细胞/巨噬细胞中过表达SuMOylated ANXA1可以显著改善小鼠脑缺血模型的神经功能。总之，我们的研究证明了一种先前未知的机制，即SUMO化的ANXA1调节小胶质细胞的极化，并强烈表明上调小胶质细胞的ANXA1 SUMO化可能为脑缺血提供治疗益处。
SUMOylation of annexin-A1 promotes an anti-inflammatory microglial phenotype and protects against cerebral ischemic injury. Annexin-A1 (ANXA1) has recently been proposed to play a role in microglial activation after brain ischemia, but the underlying mechanism remains poorly understood. Here, we demonstrated that ANXA1 is modified by SUMOylation, and SUMOylated ANXA1 could promote the beneficial phenotype polarization of microglia. Mechanistically, SUMOylated ANXA1 suppressed nuclear factor κB activation and the production of proinflammatory mediators. Further study revealed that SUMOylated ANXA1 targeted the IκB kinase (IKK) complex and selectively enhanced IKKα degradation. Simultaneously, we detected that SUMOylated ANXA1 facilitated the interaction between IKKα and NBR1 to promote IKKα degradation through selective autophagy. Further work revealed that the overexpression of SUMOylated ANXA1 in microglia/macrophages resulted in marked improvement in neurological function in a mouse model of cerebral ischemia. Collectively, our study demonstrates a previously unidentified mechanism whereby SUMOylated ANXA1 regulates microglial polarization and strongly indicates that up-regulation of ANXA1 SUMOylation in microglia may provide therapeutic benefits for cerebral ischemia.
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影响因子：
34.7
作者：
Martin, Stephane;Wilkinson, Kevin A.;Nishimune, Atsushi;Henley, Jeremy M.
通讯作者：
Henley, Jeremy M.
影响因子：
3.3
作者：
Fan, XX;Krahling, S;Schlegel, RA
通讯作者：
Schlegel, RA
芬戈莫德通过 STAT3 通路调节小胶质细胞向 M2 极化，从而防止缺血性白质损伤。
影响因子：
8.3
作者：
Qin C;Fan WH;Liu Q;Shang K;Murugan M;Wu LJ;Wang W;Tian DS
通讯作者：
Tian DS
影响因子：
14.8
作者：
Ran, F. Ann;Hsu, Patrick D.;Zhang, Feng
通讯作者：
Zhang, Feng
DOI：
10.1038/jcbfm.2011.112
发表时间：
2011-11
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
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作者：
通讯作者：
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