Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome.
GP130
IL-11
IL-6
IL6ST
LIF
STAT3
hyper-IgE syndrome
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
08
07
2020
revised:
24
01
2021
accepted:
12
02
2021
pubmed:
28
3
2021
medline:
21
10
2021
entrez:
27
3
2021
Statut:
ppublish
Résumé
Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling. Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed. We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome. Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.
Sections du résumé
BACKGROUND
Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling.
OBJECTIVE
Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants.
METHODS
We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed.
RESULTS
We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome.
CONCLUSION
Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.
Identifiants
pubmed: 33771552
pii: S0091-6749(21)00471-1
doi: 10.1016/j.jaci.2021.02.044
pii:
doi:
Substances chimiques
Cytokines
0
IL6ST protein, human
0
Cytokine Receptor gp130
133483-10-0
Types de publication
Case Reports
Clinical Trial
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
585-598Subventions
Organisme : NHGRI NIH HHS
ID : U01 HG007708
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG010218
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : U01 HG007530
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007942
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007943
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001085
Pays : United States
Informations de copyright
Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.