Recognition of pathogen-associated nucleic acids by endosomal nucleic acid-sensing toll-like receptors

Abstract

Foreign nucleic acids, the essential signature molecules of invading pathogens that act as danger signals for host cells, are detected by endosomal nucleic acid-sensing toll-like receptors (TLRs) 3, 7, 8, 9, and 13. These TLRs have evolved to recognize 'non-self' nucleic acids within endosomal compartments and rapidly initiate innate immune responses to ensure host protection through induction of type I interferons, inflammatory cytokines, chemokines, and co-stimulatory molecules and maturation of immune cells. In this review, we highlight our understanding of the recognition of pathogen-associated nucleic acids and activation of corresponding signaling pathways through endosomal nucleic acid-sensing TLRs 3, 7, 8, 9, and 13 for an enormous diversity of pathogens, with particular emphasis on their compartmentalization, intracellular trafficking, proteolytic cleavage, autophagy, and regulatory programs.

Figure 1

Overview of nucleic acid-sensing TLRs 3, 7, 8, 9, and 13 signaling pathways, compartmentalization, trafficking, and regulation mechanism Diagram showing the stimulation of TLR3, 7, 8, 9, and 13 by dsRNA, ssRNA, and CpG DNA, leading to the translocation of TLR3, 7, 8, 9, and 13 from the ER to endosomal compartments and activation of the MyD88- and TRIF-dependent signaling pathways, respectively. Upon stimulation, TLR3 recruits TRIF, which in turn recruits a set of adaptor molecules lead to the formation of a complex and the activation of IRF3, NF-κB, and AP-1. However, TLRs 7, 8, 9, and 13 interact with the TIR domain of MyD88 to recruit a set of adaptor molecules lead to the formation of a complex and the activation of IRF7, NF-κB, and AP-1. To achieve a balanced output, TLR3, 7, 8, 9, and 13 signaling pathways are positively and negatively regulated by modulatory molecules, such as A20, deubiquitinating enzyme A, SARM, SHP-2, Nrdp1, and Ubc5.