Supplementary Material for: Differential Regulation by Toll-Like Receptor Agonists Reveals That<b><i> MCPIP1</i></b> Is the Potent Regulator of Innate Immunity in Bacterial and Viral Infections

Toll-like receptors (TLRs) are key molecules in innate immunity that recognize a variety of pathogen-associated molecular patterns. Activation of TLRs by their agonists initiates several signaling cascades, which eventually result in the expression of immune modifiers. Despite the fact that MCPIP1 is reported as an important immune regulator involved in macrophage activation, modulation of its expression by all known TLR agonists has never been documented. In this study, we present for the first time that in human monocyte-derived macrophages all TLR agonists, except CpG, markedly induced the expression of MCPIP1. The level of the induced transcript, as well as the protein and time of their appearance varied depending on the agonist. Furthermore, we confirmed the strong and differential upregulation of <i>MCPIP1</i> during bacteria, virus and fungus infection. <i>MCPIP1 </i>belongs to a group of early-response genes; however, in the present study, we show for the first time the sustained high level of <i>MCPIP1 </i>expression during long-term <i>Staphylococcus aureus</i> infection. Taken together, our results implicate <i>MCPIP1</i> as a potent regulator of innate immunity, which can be strongly engaged in the pathogenesis of acute and chronic infective diseases

Exaptive origins of regulated mRNA decay in eukaryotes

Eukaryotic gene expression is extensively controlled at the level of mRNA stability and the mechanisms underlying this regulation are markedly different from their archaeal and bacterial counterparts. We propose that two such mechanisms, nonsense‐mediated decay (NMD) and motif‐specific transcript destabilization by CCCH‐type zinc finger RNA‐binding proteins, originated as a part of cellular defense against RNA pathogens. These branches of the mRNA turnover pathway might have been used by primeval eukaryotes alongside RNA interference to distinguish their own messages from those of RNA viruses and retrotransposable elements. We further hypothesize that the subsequent advent of “professional” innate and adaptive immunity systems allowed NMD and the motif‐triggered mechanisms to be efficiently repurposed for regulation of endogenous cellular transcripts. This scenario explains the rapid emergence of archetypical mRNA destabilization pathways in eukaryotes and argues that other aspects of post‐transcriptional gene regulation in this lineage might have been derived through a similar exaptation route