Self or non-self? Detection of nucleic acids in the endolysosome

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Abstract:
Self or non-self? Detection of nucleic acids in the endolysosome
A central function of our innate immune system is to detect microbial pathogens by the presence of their nucleic acid genomes or their transcriptional or replicative activity. In mammals, a receptor-based system - represented by pattern recognition receptors (PRRs) - is primarily responsible for the detection of "non-self" nucleic acids. In recent years, tremendous progress has been made in identifying the key sensing and signaling components required for this complex task. The first group of PRRs identified as nucleic acid sensing receptors are the toll-like receptors (TLRs). TLRs are expressed as transmembrane receptors with their ligand binding domain facing either the extracellular space or the luminal compartment. A distinct evolutionary subset of TLRs is located in the endolysosomal compartment, which in the human system includes TLR7, TLR8 and TLR9. While TLR9 recognizes single-stranded DNA with unmethylated CG motifs, which are indeed suppressed in the host genome, TLR7 and TLR8 have evolved to recognize RNA degradation products. Although there has been considerable research on RNA-sensing TLRs, our understanding of their capability to differentiate between non-self and self-RNA remains limited, particularly considering the prevalence of self-RNA in the endolysosomal compartment. In this talk, I will provide an update on our recent work on this topic and present some novel insights into how TLR7 and TLR8 discriminate self from non-self.