title: Cofactors required for TLR7- and TLR9-dependent innate immune responses.
abstract: 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.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Chiang
authors.forename: Alex
authors.initials: A
authors.lastname: Engel
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Opaluch
authors.forename: Irene
authors.initials: I
authors.lastname: Ramos
authors.forename: Ana M
authors.initials: AM
authors.lastname: Maestre
authors.forename: Ismael
authors.initials: I
authors.lastname: Secundino
authors.forename: Paul D
authors.initials: PD
authors.lastname: De Jesus
authors.forename: Quy T
authors.initials: QT
authors.lastname: Nguyen
authors.forename: Genevieve
authors.initials: G
authors.lastname: Welch
authors.forename: Ghislain M C
authors.initials: GM
authors.lastname: Bonamy
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Miraglia
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Orth
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.forename: Yingyao
authors.initials: Y
authors.lastname: Zhou
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Barton
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
mesh_terms: D000818:Animals; D002642:Chick Embryo; D003198:Computer Simulation; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology; D021381:Protein Transport; D034622:RNA Interference; D015398:Signal Transduction; D060388:Support Vector Machine; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D047908:Intracellular Signaling Peptides and Proteins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D010750:Phosphoproteins; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate