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S100A11 protects against neuronal cell apoptosis induced by cerebral ischemia via inhibiting the nuclear translocation of annexin A1.

ABSTRACT: The subcellular location of annexin A1 (ANXA1) determines the ultimate fate of neurons after ischemic stroke. ANXA1 nuclear translocation is involved in neuronal apoptosis after cerebral ischemia, and extracellular ANXA1 is also associated with regulation of inflammatory responses. As the factors and mechanism that influence ANXA1 subcellular translocation remain unclear, studies aiming to determine and clarify the role of ANXA1 as a cell fate 'regulator' within cells are critically needed. In this study, we found that intracerebroventricular injection of the recombinant adenovirus vector Ad-S100A11 (carrying S100A11) strongly improved cognitive function and induced robust neuroprotective effects after ischemic stroke in vivo. Furthermore, upregulation of S100A11 protected against neuronal apoptosis induced by oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro. Surprisingly, S100A11 overexpression markedly decreased ANXA1 nuclear translocation and subsequently alleviated OGD/R-induced neuronal apoptosis. Notably, S100A11 exerted its neuroprotective effect by directly binding ANXA1. Importantly, S100A11 directly interacted with ANXA1 through the nuclear translocation signal (NTS) of ANXA1, which is essential for ANXA1 to import into the nucleus. Consistent with our previous studies, ANXA1 nuclear translocation after OGD/R promoted p53 transcriptional activity, induced mRNA expression of the pro-apoptotic Bid gene, and activated the caspase-3 apoptotic pathway, which was almost completely reversed by S100A11 overexpression. Thus, S100A11 protects against cell apoptosis by inhibiting OGD/R-induced ANXA1 nuclear translocation. This study provides a novel mechanism whereby S100A11 protects against neuronal cells apoptosis, suggesting the potential for a previously unidentified treatment strategy in minimizing apoptosis after ischemic stroke.

SUBMITTER: Xia Q

PROVIDER: S-EPMC5974363 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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S100A11 protects against neuronal cell apoptosis induced by cerebral ischemia via inhibiting the nuclear translocation of annexin A1.

Xia Qian Q Li Xing X Zhou Huijuan H Zheng Lu L Shi Jing J

Cell death & disease 20180529 6

The subcellular location of annexin A1 (ANXA1) determines the ultimate fate of neurons after ischemic stroke. ANXA1 nuclear translocation is involved in neuronal apoptosis after cerebral ischemia, and extracellular ANXA1 is also associated with regulation of inflammatory responses. As the factors and mechanism that influence ANXA1 subcellular translocation remain unclear, studies aiming to determine and clarify the role of ANXA1 as a cell fate 'regulator' within cells are critically needed. In t ...[more]

PMID: 29844306

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Project description:Nuclear translocation of annexin A1 (ANXA1) has recently been reported to participate in neuronal apoptosis after cerebral ischemia. Prevention of the nuclear translocation of ANXA1 should therefore inhibit neuronal apoptosis and protect against cerebral stroke. Here, we found that, in the repeat III domain of ANXA1, the amino-acid residues from R228 to F237 function as a unique nuclear translocation signal (NTS) and are required for nuclear translocation of ANXA1. Intriguingly, we synthesized a cell-penetrating peptide derived by conjugating the trans-activator of transcription (Tat) domain to the NTS sequence. This Tat-NTS peptide specifically blocked the interaction of ANXA1 with importin ? and, consequently, the nuclear translocation of ANXA1 without affecting the nucleocytoplasmic shuttling of other proteins. The Tat-NTS peptide inhibited the transcriptional activity of p53, decreased Bid expression, suppressed activation of the caspase-3 apoptosis pathway and improved the survival of hippocampal neurons subjected to oxygen-glucose deprivation and reperfusion in vitro. Moreover, using a focal brain ischemia animal model, we showed that the Tat-NTS peptide could be efficiently infused into the ischemic hippocampus and cortex by unilateral intracerebroventricular injection. Injection of the Tat-NTS peptide alleviated neuronal apoptosis in the ischemic zone. Importantly, further work revealed that administration of the Tat-NTS peptide resulted in a dramatic reduction in infarct volume and that this was correlated with a parallel improvement in neurological function after reperfusion. Interestingly, the effects of Tat-NTS were injury specific, with little impact on neuronal apoptosis or cognitive function in sham-treated nonischemic animals. In conclusion, based on its profound neuroprotective and cognitive-preserving effects, it is suggested that the Tat-NTS peptide represents a novel and potentially promising new therapeutic candidate for the treatment of ischemic stroke.

Project description:Rationale: Annexin-A1 (ANXA1) has previously been proposed to play a crucial role in neuronal apoptosis during ischemic stroke injury. Our recent study demonstrated that ANXA1 was modified by SUMOylation, and that this modification was greatly weakened after cerebral ischemia, but its effect on neuronal death and the underlying mechanism have not been fully elucidated. Methods: Mice subjected to middle cerebral artery occlusion were established as the animal model and primary cultured neurons treated with oxygen-glucose deprivation and reperfusion was established as the cell model of ischemic stroke. The Ni2+-NTA agarose affinity pull-down assay was carried out to determine the SUMOylation level of ANXA1. Co-immunoprecipitation assays was utilized to explore the protein interaction. Immunoblot analysis, quantitative real-time PCR, Luciferase reporter assay were performed to identify the regulatory mechanism. LDH release and TUNEL staining was performed to investigate the neuronal cytotoxicity and apoptosis, respectively. Results: In this study, we identified the deSUMOylating enzyme sentrin/SUMO-specific protease 6 (SENP6) as a negative regulator of ANXA1 SUMOylation. Notably, we found that SENP6-mediated deSUMOylation of ANXA1 induced its nuclear translocation and triggered neuronal apoptosis during cerebral ischemic injury. A mechanistic study demonstrated that SENP6-mediated deSUMOylation of ANXA1 promoted TRPM7- and PKC-dependent phosphorylation of ANXA1. Furthermore, blocking the deSUMOylation of ANXA1 mediated by SENP6 inhibited the transcriptional activity of p53, decreased Bid expression, suppressed caspase-3 pathway activation and reduced the apoptosis of primary neurons subjected to oxygen-glucose deprivation and reperfusion. More importantly, SENP6 inhibition by overexpression of a SENP6 catalytic mutant in neurons resulted in significant improvement in neurological function in the mouse model of ischemic stroke. Conclusions: Taken together, the results of this study identified a previously unidentified function of SENP6 in neuronal apoptosis and strongly indicated that SENP6 inhibition may provide therapeutic benefits for cerebral ischemia.

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S100A11 protects against neuronal cell apoptosis induced by cerebral ischemia via inhibiting the nuclear translocation of annexin A1.

Publications

S100A11 protects against neuronal cell apoptosis induced by cerebral ischemia via inhibiting the nuclear translocation of annexin A1.

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