Regulatory molecules required for nucleotide-sensing Toll-like receptors.
Toll-like receptors (TLRs) play an important role in innate immune responses against bacteria and viruses. TLRs localize either on the cell surface or in intracellular vesicular compartments. The cell-surface TLRs, including TLR1, TLR2, TLR4, and TLR6, recognize microbial membrane lipids, whereas TLR3, TLR7, TLR8, and TLR9 recognize pathogen-derived nucleotides in intracellular compartments. TLR7 and TLR9 respond to host-derived nucleotides as well, and they have been implicated in a variety of autoimmune diseases. Safety mechanisms are required to avoid detrimental autoimmune responses. TLR7 and TLR9 are sequestered in the endoplasmic reticulum (ER) in a resting state and traffic to endolysosomes upon ligand-induced stimulation. Sequestration in the ER is a mechanism controlling TLR7/9 responses. A chaperone, gp96, in the ER is reported to regulate TLR7/9 maturation. gp96 is associated with TLR9 and is required for ligand-induced activation of TLR7/9. Two molecules in the ER are reported to regulate TLR7/9 trafficking to endolysosomes. PRAT4A (a protein associated with TLR4 A) is associated with TLR9 and is required for ligand-induced trafficking of TLR9 to endolysosomes. UNC93B1 is specifically associated with TLR3, TLR7, TLR9, and TLR13 and regulates ligand-induced trafficking of TLR7 and TLR9 from the ER to endolysosomes. These molecules are potential therapeutic targets for controlling dysregulated TLR7/9 responses in autoimmune diseases.
Saitoh
Shin-Ichiroh
S
Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan. shinss@ims.u-tokyo.ac.jp
Miyake
Kensuke
K
D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000628:therapy; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D004269:DNA, Bacterial / Q000276:immunology / Q000378:metabolism; D004279:DNA, Viral / Q000276:immunology / Q000378:metabolism; D018390:Gene Targeting; D006801:Humans; D026901:Membrane Transport Proteins / Q000276:immunology / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology; D012367:RNA, Viral / Q000276:immunology; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D055517:snRNP Core Proteins
D002352:Carrier Proteins; D004269:DNA, Bacterial; D004279:DNA, Viral; D026901:Membrane Transport Proteins; D053594:Myeloid Differentiation Factor 88; D012367:RNA, Viral; C508076:TLR4-associated protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C454130:UNC93B1 protein, human; D055517:snRNP Core Proteins