期刊
CELL HOST & MICROBE
卷 11, 期 3, 页码 306-318出版社
CELL PRESS
DOI: 10.1016/j.chom.2012.02.002
关键词
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资金
- Defense Threat Reduction Agency Joint Science and Technology Office (DTRA-JSTO) from the Department of Defense through the Defense Threat Reduction Agency (DTRA) [HDTRA1-07-9-0001]
- Alliance for Lupus Research Grant
- San Diego Center for Systems Biology [P50GM085764]
- National Institutes of Health (NIH) [AG032171, AI77780]
- Irvington Institute of the Cancer Research Institute
- Cancer Research Institute
- NIH/National Institute of Allergy and Infectious Diseases (NIAID) [P01 AI090935]
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 cross-profiled for their activities downstream of several immunoreceptors and then functionally mapped based on the known architecture of NF-kappa 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.
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