[PDF][PDF] Cofactors required for TLR7-and TLR9-dependent innate immune responses

C Chiang, A Engel, AM Opaluch, I Ramos… - Cell host & …, 2012 - cell.com
C Chiang, A Engel, AM Opaluch, I Ramos, AM Maestre, I Secundino, PD De Jesus…
Cell host & microbe, 2012cell.com
Pathogens 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 …
Summary
Pathogens 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.
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