Under normal physiological conditions, Toll-like receptor 7 ...

created [InstanceEdit:9824838] Shamovsky, Veronica, 2023-01-23
dbId 9824825
displayName Under normal physiological conditions, Toll-like receptor 7 ...
literatureReference
modified [InstanceEdit:9843355] Shamovsky, Veronica, 2023-09-07
schemaClass Summation
text Under normal physiological conditions, Toll-like receptor 7 (TLR7) detects uridine (U)-rich ssRNA sequences from the viral genomes including lentivirus (human immunodeficiency virus-1, HIV-1) and betacoronavirus (severe acute respiratory syndrome-associated coronavirus type 1, SARS-CoV-1 and SARS-CoV-2) (Heil F et al. 2004; Li Y et al. 2013; Campbell GR et al. 2021). TLR7 also responds to endogenous immune complexes containing self-ssRNA (Vollmer J et al., 2005; Hung T et al., 2015; Lee J et al., 2022; reviewed by Mu X et al., 2016). TLR7 may also sense small endogenous molecules such as guanosine (G), 2',3'-cyclic GMP, deoxyguanosine (dG) or 8-hydroxy-2'-deoxyguanosine (8-OHdG) (Zhang Z et al., 2016, 2018; Shibata T et al., 2016; Davenne T et al., 2020). Dysregulation of TLR7-mediated response to self-ligands may lead to an aberrant B cell signaling which is associated with the pathogenesis of autoantibody driven autoimmune diseases such as systemic lupus erythematosus (SLE) (Green NM et al., 2012; Sakata K et al., 2018). Whole-exome sequencing (WES) analysis of patients with SLE identified several TLR7 variants: R28G, Y264H and F507L (Brown GJ et al., 2022). Structural insights suggest that TLR Y264H exhibits enhanced affinity to G and 2',3'-cGMP. Thermodynamic integration method further confirmed the enhanced binding affinity of TLR Y264H to G by estimating free energy based on the molecular dynamics simulation (Brown GJ et al., 2022). Immunoblotting detected increased protein expression levels of TLR7 and MyD88 in peripheral blood mononuclear cells (PBMC) isolated from the patient with SLE carrying the Y264H variant. Enhanced NF-?appa-B activity and type I IFN responses were observed in PBMC from this SLE-patient. When introduced in mice, TLR7 Y264H induced sustained TLR7 activation triggering aberrant B cell function. Mice carrying TLR7 Y264H developed phenotypic abnormalities resembling a human SLE. In mouse macrophage RAW264. 7 cells, overexpression of TLR7 Y264H and TLR7 F507L enhanced NF-kappa-B activation in response to 2',3'-cyclic GMP, while TLR7 R28G was activated after stimulation with G in the presence of?ssRNA (Brown GJ et al., 2022).

This Reactome event shows enhanced binding of G and G analogs to gain-of-function TLR7 variants associated with SLE.

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