SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression

The functionally redundant ubiquitin E3 ligases SIAH1 and SIAH2 have been implicated in the regulation of several processes, but their role in inflammatory signaling and gene expression remains unclear. Here we have downregulated the expression of both SIAH proteins with specific siRNAs and investigated the functional consequences for IL-1a-induced gene expression and the signaling pathways activating NF-?B and AP1. The knockdown of SIAH1/2 had no significant impact on IL-1a-induced activation of NF-?B and MAPK signaling pathways, but modulated the expression of approximately one third of IL-1a-regulated genes. 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 of inflammatory gene expression. Overall design: Examining the role of SIAH1 and SIAH2 in inflammatory signaling and gene expression using RNA-seq.