Breaking self‐regulation of Regnase‐1 promotes its own protein expression
Breaking self‐regulation of Regnase‐1 promotes its own protein expression
复制标题
破坏Regnase-1的自我调节促进其自身蛋白质表达
DOI：
10.1111/gtc.13018
复制
发表时间：
2023
期刊：
影响因子：
2.1
通讯作者：
Maeda Kazuhiko
中科院分区：
文献类型：
--
作者：
Piboonprai Kitiya;Millius Arthur;Shimoda Mayuko;Tanaka Hiroki;Akira Shizuo;Maeda Kazuhiko
RNA结合蛋白（RBP）重组酶- 1是一种通过调节靶mRNA稳定性来调节免疫应答的内切酶。Regnase‐1降解一组炎症相关mrna，这有助于平衡免疫反应并有助于预防自身免疫性疾病。Regnase‐1也通过在其3'UTR中结合茎环（SL） RNA结构来切割其自身的mRNA。为了了解这种自我调节对免疫反应的重要性，我们在theRegnase - 13 ' -非翻译区（3'UTR）的靶SL中产生了2 bp基因组缺失的小鼠。这些核苷酸的缺失抑制了SL的形成，并限制了Regnase‐1介导的mRNA降解。突变小鼠的造血细胞分化正常。生物化学方面，3'UTR SL的突变增加了小鼠胚胎成纤维细胞（mef）中regnase‐1mRNA的稳定性，并提高了regnase‐1mRNA和蛋白水平。在突变mef中，重组酶1靶基因fil6的表达在稳态下被组成性抑制。此外，与野生型mef相比，在稳态和促炎细胞因子刺激下，突变mef中的Regnase‐1蛋白表达显著升高。这些数据提示了regnase‐1表达的负反馈机制，并代表了一种独特的小鼠模型来检测regnase‐1在体内的过表达。
The RNA‐binding protein (RBP) Regnase‐1 is an endonuclease that regulates immune responses by modulating target mRNA stability. Regnase‐1 degrades a group of inflammation‐associated mRNAs, which contributes to a balanced immune response and helps prevent autoimmune diseases. Regnase‐1 also cleaves its own mRNA by binding stem‐loop (SL) RNA structures in its 3′UTR. To understand how this autoregulation is important for immune responses, we generated mice with a 2‐bp genome deletion in the target SL of theRegnase‐13′‐untranslated region (3′UTR). Deletion of these nucleotides inhibited SL formation and limited Regnase‐1‐mediated mRNA degradation. Mutant mice had normal hematopoietic cell differentiation. Biochemically, mutation of the 3′UTR SL increasedRegnase‐1mRNA stability and enhanced bothRegnase‐1mRNA and protein levels in mouse embryonic fibroblasts (MEFs). The expression ofIl6, a Regnase‐1 target gene, was constitutively suppressed at steady‐state in mutant MEFs. Additionally, Regnase‐1 protein expression in mutant MEFs was significantly elevated compared to that in wild‐type MEFs at steady state and upon proinflammatory cytokine stimulation. These data suggest a negative feedback mechanism forRegnase‐1expression and represent a unique mouse model to probeRegnase‐1overexpression in vivo.
影响因子：
11.2
作者：
Lu W;Ning H;Gu L;Peng H;Wang Q;Hou R;Fu M;Hoft DF;Liu J
通讯作者：
Liu J
影响因子：
4.6
作者：
Wilamowski M;Gorecki A;Dziedzicka-Wasylewska M;Jura J
通讯作者：
Jura J
影响因子：
30.5
作者：
Jeltsch, Katharina M.;Hu, Desheng;Heissmeyer, Vigo
通讯作者：
Heissmeyer, Vigo