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Identification and characterization of novel innate immune signaling regulators


The recognition of foreign pathogens by innate pattern recognition receptors (PRRs) serves as the first line of defense against harmful microorganisms. One family of PRRs, known as Toll-like receptors (TLRs), are expressed on plasma and endocytic membranes in order to detect extracellular or endocytosed bacteria-, fungus-, or virus- derived ligands. The sensing of pathogen-encoded patterns by TLRs activates these receptors, which transmit downstream signals resulting in the activation of NF- [kappa]B transcription factors and the production of pro- inflammatory cytokines, as well as the activation of IRF (interferon regulatory factor) transcription factors and the induction of type I interferons. The production of both mediators is critical for the immediate innate response to pathogen infection and for further signaling to engage long-term adaptive immune responses. Altogether, these pathways are exquisitely regulated to ensure clearance of invading microbes while limiting harmful autoimmune responses. Here, we report the characterization of novel regulatory co-factors that are required for TLR- directed innate immune signaling responses. These factors were identified using two screening approaches. First, the set of cellular components associated with TLR7- and TLR9- dependent responses were uncovered using an integrative systems-based genome-wide RNAi screen. This loss-of- function screen characterized 190 genes necessary for TLR7 /9 signaling, and further mapped 90 of these factors to a relative position on the TLR signaling cascade. HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) was also found to be essential for the ubiquitin-dependent targeting of TLR9 to endolysosomes. Second, a biased gain-of-function screening approach was used to identify genes that increased NF-[kappa]B signaling. This method classified the gamma subunit of protein phosphatase 1 (PP1-[gamma]) as a specific regulator of MyD88-dependent pro-inflammatory responses, and a more extensive mechanistic study demonstrated that PP1-[gamma] enhances the E3 ubiquitin ligase activity of TRAF6 towards itself and IKK--[gamma]. Collectively, this analysis has identified proteins that are critical regulators of TLR-dependent innate responses and has provided significant insight into the molecular events underlying this complex signaling pathway

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