Cofactors Required for TLR7- and TLR9-Dependent Innate Immune Responses

SummaryPathogens commonly utilize endocytic pathways to gain cellular access. The endosomal pattern recognition receptors TLR7 and TLR9 detect pathogen-encoded nucleic acids to initiate MyD88-dependent proinflammatory responses to microbial infection. Using genome-wide RNAi screening and integrative systems-based analysis, we identify 190 cofactors required for TLR7- and TLR9-directed signaling responses. A set of cofactors were crossprofiled for their activities downstream of several immunoreceptors and then functionally mapped based on the known architecture of NF-κB signaling pathways. Protein complexes and pathways involved in ubiquitin-protein ligase activities, sphingolipid metabolism, chromatin modifications, and ancient stress responses were found to modulate innate recognition of endosomal nucleic acids. Additionally, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) was characterized as necessary for ubiquitin-dependent TLR9 targeting to the endolysosome. Proteins and pathways identified here should prove useful in delineating strategies to manipulate innate responses for treatment of autoimmune disorders and microbial infection.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (491 K)Download as PowerPoint slideHighlights► RNAi and systems-based analysis identified 190 TLR7/9 signaling cofactors ► Pathway crossprofiling enabled mapping cofactors to specific NFκB signaling modules ► HRS is a mediator of ubiquitin-dependent nondegradative endosomal TLR sorting