title: UNC93B1 is essential for TLR11 activation and IL-12-dependent host resistance to Toxoplasma gondii.
abstract: Toll-like receptor (TLR) activation relies on biochemical recognition of microbial molecules and localization of the TLR within specific cellular compartments. Cell surface TLRs largely recognize bacterial membrane components, and intracellular TLRs are exclusively involved in sensing nucleic acids. Here we show that TLR11, an innate sensor for the Toxoplasma protein profilin, is an intracellular receptor that resides in the endoplasmic reticulum. The 12 membrane-spanning endoplasmic reticulum-resident protein UNC93B1 interacts directly with TLR11 and regulates the activation of dendritic cells in response to Toxoplasma gondii profilin and parasitic infection in vivo. A deficiency in functional UNC93B1 protein abolished TLR11-dependent IL-12 secretion by dendritic cells, attenuated Th1 responses against T. gondii, and dramatically enhanced susceptibility to the parasite. Our results reveal that the association with UNC93B1 and the intracellular localization of TLRs are not unique features of nucleic acid-sensing TLRs but is also essential for TLR11-dependent recognition of T. gondii profilin and for host protection against this parasite.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9093, USA.
authors.forename: Reed
authors.initials: R
authors.lastname: Pifer
authors.forename: Alicia
authors.initials: A
authors.lastname: Benson
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Sturge
authors.forename: Felix
authors.initials: F
authors.lastname: Yarovinsky
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D007109:Immunity; D018664:Interleukin-12 / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051304:Profilins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000032:analysis / Q000172:deficiency / Q000378:metabolism*; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000469:parasitology
chemical_list: D026901:Membrane Transport Proteins; D051304:Profilins; C482903:Tlr11 protein, mouse; D051193:Toll-Like Receptors; C512254:UNC93B1 protein, mouse; D018664:Interleukin-12