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Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKK? stability via selective autophagy.


ABSTRACT: 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 ?B activation and the production of proinflammatory mediators. Further study revealed that SUMOylated ANXA1 targeted the I?B kinase (IKK) complex and selectively enhanced IKK? degradation. Simultaneously, we detected that SUMOylated ANXA1 facilitated the interaction between IKK? and NBR1 to promote IKK? 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.

SUBMITTER: Li X 

PROVIDER: S-EPMC7817101 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKKα stability via selective autophagy.

Li Xing X   Xia Qian Q   Xia Qian Q   Mao Meng M   Zhou Huijuan H   Zheng Lu L   Wang Yi Y   Zeng Zhen Z   Yan Lulu L   Zhao Yin Y   Shi Jing J  

Science advances 20210120 4


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 kin  ...[more]

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