G or G analog binds C-ter TLR7 GoF variant

Stable Identifier
R-HSA-9824849
Type
Reaction [binding]
Species
Homo sapiens
Compartment
endolysosome lumen, endolysosome membrane
ReviewStatus
3/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
G or G analog binds C-ter TLR7 GoF variant
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
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-κappa-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.

Literature References
PubMed ID Title Journal Year
35477763 TLR7 gain-of-function genetic variation causes human lupus

Ding, H, Lopez, AF, Calame, DG, Levy, T, Andrews, TD, Field, MA, Lupski, JR, Shen, N, Burgio, G, Miosge, LA, Garulo, DC, Koina, ME, de Lucas Collantes, C, Wu, P, Vinuesa, CG, He, Y, Meng, X, Mallack, EJ, Cho, E, Bassett, K, Babon, JJ, Brown, GJ, Wang, H, Lotze, T, Zhang, Y, Turnbull, C, Ullah, TR, Cañete, PF, Qin, Y, Shen, Q, Gantier, MP, Ellyard, JI, Gónzalez-Murillo, Á, Tvorogov, D, Cook, MC, Cappello, J, Walters, GD, Athanasopoulos, V, Pascual, V, Medhavy, A, Roco, JA, Bones, J, López, CA, Corry, B

Nature 2022
Participants
Input
Output
Participates
as an event of
Normal reaction
G or G analog binds C-ter TLR7 dimer (Homo sapiens)
Functional status

Gain of function of C-ter TLR7 variant dimer [endolysosome membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
systemic lupus erythematosus DOID:9074 Lupus Erythematosus, systemic, SLE - Lupus Erythematosus, systemic, disseminated lupus erythematosus
autoimmune hypersensitivity disease DOID:417 autoimmune disease, hypersensitivity reaction type II disease
Authored
Shamovsky, V  (2023-01-23)
Created
Shamovsky, V  (2023-01-23)
Cite Us!