Zybura-Broda Katarzyna, Wolder-Gontarek Malgorzata, Ambrozek-Latecka Magdalena, Choros Artur, Bogusz Agnieszka, Wilemska-Dziaduszycka Joanna, Rylski Marcin
Department of Clinical Cytology, Centre of Postgraduate Medical Education, Warsaw, Poland.
Front Neurosci. 2018 Apr 9;12:224. doi: 10.3389/fnins.2018.00224. eCollection 2018.
Matrix metalloproteinase-9 (Mmp-9) is involved in different general and cell-type-specific processes, both in neuronal and non-neuronal cells. Moreover, it is implicated in an induction or progression of various human disorders, including diseases of the central nervous system. Mechanisms regulating activity-driven Mmp-9 expression in neurons are still not fully understood. Here, we show that stabilization of Mmp-9 mRNA is one of the factors responsible for the neuronal activity-evoked upregulation of Mmp-9 mRNA expression in hippocampal neurons. Furthermore, we demonstrate that the molecular mechanism related to this stabilization is dependent on the neuronal seizure-triggered transiently increased binding of the mRNA stability-inducing protein, HuR, to ARE1 and ARE4 motifs of the 3'UTR for Mmp-9 mRNA as well as the stably augmented association of another mRNA-stabilizing protein, HuB, to the ARE1 element of the 3'UTR. Intriguingly, we demonstrate further that both HuR and HuB are crucial for an incidence of Mmp-9 mRNA stabilization after neuronal activation. This study identifies Mmp-9 mRNA as the first HuB target regulated by mRNA stabilization in neurons. Moreover, these results are the first to describe an existence of HuR-dependent mRNA stabilization in neurons of the brain.
基质金属蛋白酶-9（Mmp-9）参与神经元和非神经元细胞中的不同一般过程及细胞类型特异性过程。此外，它还与包括中枢神经系统疾病在内的各种人类疾病的诱导或进展有关。调节神经元中活性驱动的Mmp-9表达的机制仍未完全了解。在此，我们表明Mmp-9 mRNA的稳定性是海马神经元中神经元活动诱发的Mmp-9 mRNA表达上调的原因之一。此外，我们证明与这种稳定性相关的分子机制取决于神经元癫痫发作触发的mRNA稳定性诱导蛋白HuR与Mmp-9 mRNA 3'UTR的ARE1和ARE4基序的瞬时增加结合，以及另一种mRNA稳定蛋白HuB与3'UTR的ARE1元件的稳定增强结合。有趣的是，我们进一步证明HuR和HuB对于神经元激活后Mmp-9 mRNA稳定性的发生至关重要。本研究确定Mmp-9 mRNA是神经元中第一个受mRNA稳定性调节的HuB靶标。此外，这些结果首次描述了大脑神经元中存在HuR依赖性mRNA稳定性。
