Schmitz M Lienhard, Dreute Jan, Pfisterer Maximilian, Günther Stefan, Kracht Michael, Chillappagari Shashipavan
Institute of Biochemistry, Justus-Liebig-University, D-35392, Giessen, Germany.
Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, D-61231, Bad Nauheim, Germany.
Heliyon. 2022 Mar 1;8(3):e09029. doi: 10.1016/j.heliyon.2022.e09029. eCollection 2022 Mar.
The functionally redundant ubiquitin E3 ligases SIAH1 and SIAH2 have been implicated in the regulation of metabolism and the hypoxic response, while their role in other signal-mediated processes such inflammatory gene expression remains to be defined. Here we have downregulated the expression of both SIAH proteins with specific siRNAs and investigated the functional consequences for IL-1α-induced gene expression. The knockdown of SIAH1/2 modulated the expression of approximately one third of IL-1α-regulated genes. These effects were not due to changes in the NF-κB and MAPK signaling pathways and rather employed further processes including those mediated by the coactivator p300. Most of the proteins encoded by SIAH1/2-regulated genes form a regulatory network of proinflammatory factors. Thus SIAH1/2 proteins function as variable rheostats that control the amplitude rather than the principal activation of the inflammatory gene response.
功能冗余的泛素E3连接酶SIAH1和SIAH2与代谢调节和缺氧反应有关，而它们在其他信号介导的过程（如炎症基因表达）中的作用仍有待确定。在这里，我们用特异性小干扰RNA（siRNA）下调了两种SIAH蛋白的表达，并研究了对IL-1α诱导的基因表达的功能影响。SIAH1/2的敲低调节了大约三分之一的IL-1α调节基因的表达。这些作用并非由于NF-κB和丝裂原活化蛋白激酶（MAPK）信号通路的变化，而是涉及包括共激活因子p300介导的过程在内的其他过程。SIAH1/2调节基因编码的大多数蛋白质形成了一个促炎因子调节网络。因此，SIAH1/2蛋白起着可变变阻器的作用，控制炎症基因反应的幅度而非主要激活。
