Gene Ontology annotation through association of InterPro records with GO terms.
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
Automatic assignment of GO terms using logical inference, based on on inter-ontology links.
Combined Automated Annotation using Multiple IEA Methods.
IL1HY1: A novel interleukin-1 receptor antagonist gene.
Towards a proteome-scale map of the human protein-protein interaction network.
The IL-36 receptor pathway regulates Aspergillus fumigatus-induced Th1 and Th17 responses.
A proteome-scale map of the human interactome network.
A reference map of the human binary protein interactome.
IL-36 cytokines in inflammatory and malignant diseases: not the new kid on the block anymore.
IL36RN, IL1F10 bind IL1RL2
Deep research on IL36RN function
Falcon deep research on IL36RN function (Edison Scientific Literature)
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IL-36Ra binds the IL-36 receptor complex but does not support productive accessory-protein recruitment, thereby competitively inhibiting IL-36 signaling; downstream nodes include MyD88, NF-kB, and MAPK.
"IL-36 agonists (IL-36α/β/γ) signal through **IL‑36R** with recruitment of the accessory protein **IL‑1RAcP**, triggering downstream inflammatory pathways including **MyD88**, **NF‑κB**, and **MAPK** activation; **IL‑36Ra** binds the IL‑36 receptor complex but does **not** support productive accessory‑protein recruitment, thereby competitively inhibiting IL‑36 signaling."
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Neutrophil elastase cleaves IL-36Ra into a highly active antagonistic form; in primary skin cells the processed form dose-dependently reduces IL-36-gamma-induced IL-8 and CCL20.
"**IL‑36Ra processing:** A key primary study demonstrated that **neutrophil elastase** (but not other tested neutrophil proteases) cleaves IL‑36Ra into a **highly active antagonistic form** and that this processed IL‑36Ra more strongly suppresses IL‑36γ‑induced chemokines."
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Loss-of-function IL36RN variants cause DITRA and are strongly enriched in GPP-only versus GPP with plaque psoriasis.
"Loss‑of‑function IL36RN variants cause **deficiency of interleukin‑36 receptor antagonist (DITRA)** and are strongly linked to severe pustular phenotypes including GPP, consistent with a mechanism of **unopposed IL‑36 signaling** and exaggerated neutrophilic inflammation."
Neutrophil Elastase-mediated proteolysis activates the anti-inflammatory cytokine IL-36 Receptor antagonist.
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Neutrophil elastase (but not cathepsin G or proteinase 3) cleaves IL-36Ra precisely 9 amino acids upstream of the A-X-D motif to generate the mature active V2 form.
"Analysis of the incubations by SDS-PAGE indicated that neutrophil elastase efficiently cleaved IL-36Ra, compared to proteinase 3 and cathepsin G which had much lower cleavage activity (Fig. 3). Further analysis of the cleaved products by mass spectrometry and N-terminal sequencing identified the truncations generated (shown in table 1) and revealed that elastase cleaved IL-36Ra precisely 9 amino acids upstream of its A-X-D motif to the mature IL-36Ra V2 form"
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Mature IL-36Ra V2, but not full-length IL-36Ra, antagonizes IL-36 agonist stimulation and reduces IL-8 and CCL20 in primary fibroblasts, keratinocytes, and skin equivalents.
"In both monolayer cultures and skin equivalents, full length IL-36Ra exhibited no antagonistic activity, whilst the IL-36Ra V2 truncation antagonised IL-36 agonist stimulation causing a significant reduction in both IL-8 and CCL20 expression (Fig. 4C)."
The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab.
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IL-36 cytokines signal via IL-36R/IL-1RAcP through MyD88, IRAK, and TRAF to activate MAPK and NF-kB; IL-36Ra competitively binds IL-36R and blocks this pathway.
"Formation of the receptor complex recruits intracellular adaptor proteins, including myeloid differentiation primary response 88 (Myd88), IL-1 receptor-associated kinase (IRAK), and TNF receptor-associated factor, which subsequently activate mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NFκB) pathways. NFκB upregulates a broad range of pro-inflammatory gene products. IL-1 and IL-36 cytokines are negatively regulated by their receptor antagonist (IL-1Ra and IL-36Ra, respectively), via competitive binding for the receptor site"
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DITRA arises from autosomal recessive loss-of-function IL36RN mutations and presents with severe GPP.
"DIRA and DITRA represent autosomal recessive loss-of-function mutations in genes IL1RN and IL36RN, respectively"
Targeted review of IL36RN mutations in patients with generalised pustular psoriasis.
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IL36RN mutations are significantly enriched in GPP-only vs GPP+plaque psoriasis (OR 3.51; 95% CI 2.29-5.38), with biallelic variants in up to 73.2% of GPP patients.
"Meta-analyses showed a significantly higher rate of IL36RN mutations in the GPP-only population compared to the GPP + plaque PsO population (OR 3.51; 95% CI 2.29, 5.38). Monoallelic mutations of IL36RN were found in up to 33.3%, and biallelic mutations in up to 73.2% of patients with GPP"