Co-factors Required for TLR7- and TLR9- dependent Innate Immune Responses

• Published in: Cell host & microbe 2012-03, Vol.11 (3), p.306-318
• Main Authors: Chiang, Chih-yuan, Engel, Alex, Opaluch, Amanda M., Ramos, Irene, Maestre, Ana M., Secundino, Ismael, De Jesus, Paul D., Nguyen, Quy T., Welch, Genevieve, Bonamy, Ghislain M.C., Miraglia, Loren J., Orth, Anthony P., Nizet, Victor, Fernandez-Sesma, Ana, Zhou, Yingyao, Barton, Gregory M., Chanda, Sumit K.
• Format: Article
• Language: English
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2012.02.002

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 pro-inflammatory responses to microbial infection. Using genome-wide RNAi screening and integrative systems-based analysis we identify 190 co-factors required for TLR7- and TLR9-directed signaling responses. A set of co-factors were cross-profiled 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.