Cofactors required for TLR7- and TLR9-dependent innate immune responses
Por:
Chiang C.-Y., Engel A., Opaluch A.M., Ramos I., Maestre A.M., Secundino I., De Jesus P.D., Nguyen Q.T., Welch G., Bonamy G.M.C., Miraglia L.J., Orth A.P., Nizet V., Fernandez-Sesma A., Zhou Y., Barton G.M., Chanda S.K.
Publicada:
1 ene 2012
Resumen:
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-?B 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. © 2012 Elsevier Inc.
Filiaciones:
Chiang C.-Y.:
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, San Diego, CA 92037, United States
Engel A.:
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3200, United States
Opaluch A.M.:
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, San Diego, CA 92037, United States
Ramos I.:
Department of Microbiology, Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029, United States
Maestre A.M.:
Department of Microbiology, Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029, United States
Secundino I.:
Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, United States
De Jesus P.D.:
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, San Diego, CA 92037, United States
Nguyen Q.T.:
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, San Diego, CA 92037, United States
Welch G.:
Genomics Institute, Novartis Research Foundation, San Diego, CA 92121, United States
Bonamy G.M.C.:
Genomics Institute, Novartis Research Foundation, San Diego, CA 92121, United States
Hudson-Alpha Institute for Biotechnology, Huntsville, AL 35801, United States
Miraglia L.J.:
Genomics Institute, Novartis Research Foundation, San Diego, CA 92121, United States
Orth A.P.:
Genomics Institute, Novartis Research Foundation, San Diego, CA 92121, United States
Nizet V.:
Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, United States
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA 92093, United States
Fernandez-Sesma A.:
Department of Microbiology, Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029, United States
Zhou Y.:
Genomics Institute, Novartis Research Foundation, San Diego, CA 92121, United States
Barton G.M.:
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3200, United States
Chanda S.K.:
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, San Diego, CA 92037, United States
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