The homeostatic function of Regnase-2 restricts neuroinflammation.
The homeostatic function of Regnase-2 restricts neuroinflammation.
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DOI：
10.1096/fj.202201978r
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发表时间：
2023-03
期刊：
影响因子：
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调节RNase Regnase-2（Reg-2/ZC 3 H12 B/MCPIP 2）活性的精确生理功能和机制仍然是个谜。我们发现Reg-2积极调节非转化细胞（包括原代星形胶质细胞）中的神经炎症。这些细胞中Reg-2的下调导致促炎细胞因子IL-1β和IL-6的mRNA水平增加。在原代星形胶质细胞中，Reg-2还调节Regnase-1（Reg-1/ZC 3 H12 A/MCPIP 1）的mRNA水平。Reg-2在健康大脑中以高水平表达，但其表达在神经炎症以及胶质母细胞瘤进展期间减少。这一过程与Reg-1的上调有关。相反，Reg-2的过表达伴随着神经胶质瘤细胞中Reg-1以溶核NYN/PIN结构域依赖性方式的下调。有趣的是，低水平的Reg-2和高水平的Reg-1与胶质母细胞瘤患者的预后不良相关。虽然Reg-2限制静息星形胶质细胞中促炎细胞因子的基础水平，但其表达在IL-1β激活的星形胶质细胞中减少。在IL-1β暴露后，Reg-2被磷酸化、泛素化并被蛋白酶体降解。同时，Reg-2转录物通过其3 'UTR中存在的战神元件和保守茎环结构被三曲脯氨酸（TTP）和Reg-1去稳定。因此，存在彼此相对的Reg-1和Reg-2的对等控制环路。TTP参与Reg-2 mRNA周转的观察结果证实了高TTP水平与高级别人胶质瘤中Reg-2表达的下调相关。此外，获得的结果揭示了Reg-2在抑制人和小鼠胶质瘤细胞增殖中的重要性。我们目前的研究将Reg-2确定为大脑内稳态的关键调节因子。
The precise physiological functions and mechanisms regulating RNase Regnase-2 (Reg-2/ZC3H12B/MCPIP2) activity remain enigmatic. We found that Reg-2 actively modulates neuroinflammation in non-transformed cells, including primary astrocytes. Down-regulation of Reg-2 in these cells results in increased mRNA levels of proinflammatory cytokines IL-1β and IL-6. In primary astrocytes, Reg-2 also regulates the mRNA level of Regnase-1 (Reg-1/ZC3H12A/MCPIP1). Reg-2 is expressed at high levels in the healthy brain, but its expression is reduced during neuroinflammation as well as glioblastoma progression. This process is associated with the upregulation of Reg-1. Conversely, overexpression of Reg-2 is accompanied by the downregulation of Reg-1 in glioma cells in a nucleolytic NYN/PIN domain-dependent manner. Interestingly, low levels of Reg-2 and high levels of Reg-1 correlate with poor glioblastoma patients’ prognoses. While Reg-2 restricts the basal levels of proinflammatory cytokines in resting astrocytes, its expression is reduced in IL-1β-activated astrocytes. Following IL-1β exposure, Reg-2 is phosphorylated, ubiquitinated, and degraded by proteasomes. Simultaneously, the Reg-2 transcript is destabilized by tristetraprolin (TTP) and Reg-1 through the AREs elements and conservative stem-loop structure present in its 3’UTR. Thus, the peer-control loop, of Reg-1 and Reg-2 opposing each other, exists. The involvement of TTP in Reg-2 mRNA turnover is confirmed by the observation that high TTP levels correlate with the downregulation of the Reg-2 expression in high-grade human gliomas. Additionally, obtained results reveal the importance of Reg-2 in inhibiting human and mouse glioma cell proliferation. Our current studies identify Reg-2 as a critical regulator of homeostasis in the brain.
DOI：
10.1016/j.omtn.2021.09.004
发表时间：
2021-12-03
期刊：
Molecular therapy. Nucleic acids
影响因子：
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作者：
Czarnek M;Sarad K;Karaś A;Kochan J;Bereta J
通讯作者：
Bereta J