Laboratory of Host Defense, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Cell. 2013 May 23;153(5):1036-49. doi: 10.1016/j.cell.2013.04.034.
Regnase-1 (also known as Zc3h12a and MCPIP1) is an RNase that destabilizes a set of mRNAs, including Il6 and Il12b, through cleavage of their 3' UTRs. Although Regnase-1 inactivation leads to development of an autoimmune disease characterized by T cell activation and hyperimmunoglobulinemia in mice, the mechanism of Regnase-1-mediated immune regulation has remained unclear. We show that Regnase-1 is essential for preventing aberrant effector CD4(+) T cell generation cell autonomously. Moreover, in T cells, Regnase-1 regulates the mRNAs of a set of genes, including c-Rel, Ox40, and Il2, through cleavage of their 3' UTRs. Interestingly, T cell receptor (TCR) stimulation leads to cleavage of Regnase-1 at R111 by Malt1/paracaspase, freeing T cells from Regnase-1-mediated suppression. Furthermore, Malt1 protease activity is critical for controlling the mRNA stability of T cell effector genes. Collectively, these results indicate that dynamic control of Regnase-1 expression in T cells is critical for controlling T cell activation.
Regnase-1（也称为 Zc3h12a 和 MCPIP1）是一种 RNase，通过切割其 3'UTR 使包括 Il6 和 Il12b 在内的一组 mRNA 不稳定。尽管 Regnase-1 的失活导致了一种自身免疫疾病的发展，其特征是小鼠 T 细胞的激活和高免疫球蛋白血症，但 Regnase-1 介导的免疫调节机制仍不清楚。我们表明，Regnase-1 对于防止自身免疫疾病的发生是必需的。此外，在 T 细胞中，Regnase-1 通过切割其 3'UTR 来调节一组基因的 mRNA，包括 c-Rel、Ox40 和 Il2。有趣的是，T 细胞受体（TCR）刺激导致 Malt1/半胱天冬酶切割 Regnase-1 的 R111，从而使 T 细胞摆脱 Regnase-1 介导的抑制。此外，Malt1 蛋白酶活性对于控制 T 细胞效应基因的 mRNA 稳定性至关重要。总之，这些结果表明 T 细胞中 Regnase-1 表达的动态控制对于控制 T 细胞的激活至关重要。
