Journal Article

PUBDB-2026-01367

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome

Skenteris, N. T. (Corresponding author) ; Luttermann, E. ; Nair, S. ; Evangelakos, I. ; Pujantell, M. ; Eggers, M. ; Hausmann, F. ; Bérouti, M. ; Padoan, B. ; Flomm, F. J. ; Claussen, J. M. ; Grünhagel, B. ; Salfelder, A. ; Beifuss, B. ; Biskup, S. ; Blümke, P. ; Rading, K. ; Hildebrandt, H. ; Matschl, U. ; Giesemann-Jansen, S. ; Hennesen, J. ; Nikolaev, V. O. ; Kutsche, M. ; Kubisch, C. ; Koch-Nolte, F. ; Tomas, N. M. ; Tolosa, E. ; Lütgehetmann, M. ; Stahl, F. R. ; Hornung, V. ; Bunders, M. J. ; Schlein, C. ; Topf, M.Extern*CSSB* ; Kötter, I. ; Altfeld, M.

2026
JCI Insight Ann Arbor, Michigan

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Please use a persistent id in citations: doi:10.1172/jci.insight.187422  doi:10.3204/PUBDB-2026-01367

Abstract: With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Establishing pathogenicity requires a multidisciplinary approach that integrates genetic, structural, functional, and clinical data. Here, we used such a strategy to investigate a previously unreported hemizygous missense variant — alanine (A) to threonine (T) at residue 518 — in Toll-like receptor 8 (TLR8), identified in 2 male siblings with recurrent infections and systemic inflammation, characterized by a proinflammatory immune signature and B cell dysregulation. Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect. Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation. Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution. Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in 2 siblings.

Note: DFG CRC1648.

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Contributing Institute(s):

1. CSSB - Leibniz-Institut für Experimentelle Virologie (LIV) / UKE - Maya Topf (CSSB-LIV/UKE-MT)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)
2. DFG project G:(GEPRIS)429191104 - FOR 5068: Geschlechtsspezifische Unterschiede in Immunantworten (429191104) (429191104)
3. DFG project G:(GEPRIS)450149205 - TRR 333: Braunes und beiges Fett - Organinteraktionen, Signalwege und Energiehaushalt (BATenergy) (450149205) (450149205)

Experiment(s):

1. No specific instrument

Appears in the scientific report 2026

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Database coverage:
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