The homeostatic function of Regnase‐2 restricts neuroinflammation

Abstract

AbstractThe 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 nontransformed cells, including primary astrocytes. Downregulation 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.