IL17RA Human

What is the basic structure of human IL17RA?

Human IL17RA (IL-17R) is an 866 amino acid type I membrane glycoprotein with a molecular weight of approximately 120 kDa. It comprises three main structural domains: a 293 amino acid extracellular domain (ECD), a 21 amino acid transmembrane domain, and a 525 amino acid cytoplasmic tail. The extracellular portion spans from Leu33 to Trp320 and shares approximately 72% amino acid sequence identity with mouse and rat IL-17R . The receptor contains several conserved motifs in its cytoplasmic domain that facilitate downstream signaling events.

How is IL17RA expression regulated across different tissues?

Unlike its ligand IL-17 (CTLA-8), which is primarily expressed in activated T cells, IL17RA exhibits remarkably broad tissue distribution. The receptor's mRNA has been detected in virtually all cells and tissues tested, making it one of the most ubiquitously expressed cytokine receptors . This wide distribution pattern suggests a multifaceted role in various physiological processes beyond immune function. Researchers should consider this broad expression pattern when designing tissue-specific knockout or inhibition experiments.

What signaling pathways are activated downstream of IL17RA?

IL17RA signaling primarily activates NF-κB and JNK pathways through a mechanism requiring TNF receptor-associated factor 6 (TRAF6) . When IL-17A or IL-17F binds to the receptor, it triggers the formation of receptor heterodimers with IL17RC or IL17RD, respectively. This dimerization event initiates signaling cascades that ultimately regulate inflammatory gene expression. Signaling through IL17RA influences neutrophil mobilization, attraction, and activation, serving as a bridge between innate and adaptive immune responses .

What are reliable methods to detect IL17RA expression in different cell types?

For optimal detection of IL17RA expression, researchers should employ a multi-method approach:

• Flow cytometry: Using fluorophore-conjugated antibodies (such as Alexa Fluor 647-conjugated anti-IL17RA) enables precise quantification of surface expression in various cell populations including lymphocytes, monocytes, and neutrophils . Cell sorting techniques can further refine analysis in specific subpopulations.

• Immunofluorescence microscopy: This approach allows visualization of receptor localization within cells. As demonstrated in studies using HEK293 and HaCat cells transfected with HA-tagged IL17RA constructs, both wild-type and mutant variants can be assessed for membrane localization .

• Western blotting: For protein expression level analysis, western blotting using specific antibodies against IL17RA provides quantitative information about expression levels and any processing variations.

• RT-qPCR: Transcriptional analysis complements protein detection methods and can reveal tissue-specific regulation of IL17RA expression.

How can researchers effectively study IL17RA-mediated signaling pathways?

To investigate IL17RA signaling pathways, researchers should consider these methodological approaches:

• Co-immunoprecipitation assays: These are essential for studying physical interactions between IL17RA and its binding partners (IL17RC, IL17RD) or downstream signaling molecules. For instance, using Flag-tagged IL17RC or IL17RD along with HA-tagged IL17RA constructs allows precise assessment of protein-protein interactions through immunoprecipitation with anti-Flag antibodies followed by western blot detection with anti-HA antibodies .

• Reporter assays: NF-κB or JNK pathway activation can be monitored using luciferase reporter systems transfected into relevant cell lines.

• Phosphorylation analysis: Examining the phosphorylation status of downstream signaling molecules provides insights into pathway activation kinetics.

• Transcriptomic analysis: RNA sequencing of cells with normal or disrupted IL17RA function can reveal the full spectrum of genes regulated by this signaling pathway, as demonstrated in skin biopsy analyses that revealed distinct inflammatory signatures .

What are the known associations between IL17RA mutations and disease states?

IL17RA mutations have been linked to several immunological and inflammatory conditions:

• Chronic mucocutaneous candidiasis (CMC): Loss-of-function mutations in IL17RA have been associated with susceptibility to CMC, highlighting the receptor's role in antifungal immunity. Recent research has identified a novel bi-allelic variant (NM_014339.6, c.1173C>G A) resulting in a premature stop codon (p. Tyr391Ter) that was linked to CMC in a pediatric patient .

• Psoriasis: The same truncation variant of IL17RA (p. Tyr391Ter) that remains functionally capable of dimerizing with IL17RC and IL17RD has been linked to psoriatic phenotypes. Transcriptomic analysis of affected skin showed a distinct psoriasis-associated signature intertwined with inflammatory pathways, including responses to fungal infections .

• Skin barrier dysfunction: IL17RA deficiency leads to aberrant filaggrin expression in the skin, resulting in defective skin barrier function and cutaneous inflammation associated with eosinophilia and elevated IL-5 and TSLP levels .

How does IL17RA contribute to skin barrier maintenance?

IL17RA plays a crucial role in skin barrier integrity through several mechanisms:

• Filaggrin regulation: IL17RA deficient mice exhibit aberrant filaggrin expression, a key protein for skin barrier function. This alteration contributes to barrier defects and increased susceptibility to environmental triggers .

• Microbiome regulation: IL17RA deficiency results in skin microbiome dysbiosis. Studies have shown that antibiotic treatment ameliorates skin inflammation in IL17RA-deficient models, suggesting a relationship between IL17RA, skin microbiota, and inflammatory responses .

• Immune cell modulation: IL17RA deficiency leads to expansion of IL-5 producing pathogenic effector Th2 (peTh2) cells and development of CD4+ T cell-dependent allergic skin inflammation .

• TSLP pathway regulation: Deficiency in TSLP-mediated signals restored barrier homeostasis and protected from the development of spontaneous allergic skin inflammation in IL17RA-deficient models, indicating a regulatory relationship between these pathways .

How do IL17RA heterodimeric complexes influence signaling specificity?

IL17RA forms heterodimeric complexes with different partners to mediate specific signaling outcomes:

• IL17RA/IL17RC complex: This heterodimer primarily responds to IL17A and IL17F ligands. The structural arrangement involves a hexameric assembly with unique receptor recognition properties that determine signaling specificity .

• IL17RA/IL17RD complex: This alternative complex formation provides additional versatility in response to different IL17 family cytokines.
  The formation of these distinct heterodimeric complexes enables fine-tuned responses to various inflammatory stimuli. Recent structural insights have revealed that IL17 signaling involves formation of a hexameric complex with a two-faced cytokine signature, explaining how different combinations of receptor subunits can yield distinct biological outcomes .

What are the seemingly paradoxical effects of IL17RA signaling in different disease contexts?

IL17RA signaling demonstrates context-dependent effects that may appear contradictory:

• In fungal immunity vs. autoimmunity: While IL17 signaling provides essential protection against extracellular pathogens (particularly fungi), excessive activation promotes inflammatory pathology in autoimmune diseases like psoriasis .

• In skin barrier function: IL17RA deficiency unexpectedly exacerbates rather than ameliorates skin inflammation in filaggrin-mutant mice. IL17RA-deficient mice develop spontaneous and progressive skin inflammation regardless of filaggrin mutation status, contradicting the expected protective effect of blocking pro-inflammatory IL17 signaling .

• Feedback mechanisms: Loss of function of IL17RA in keratinocytes can trigger feedback mechanisms resulting in hyperproduction of IL17 in the skin and recruitment of more Th17 cells. This was observed in IL17RA knockout mice, which exhibited significantly elevated levels of Th17- and IL17A-producing dermal γδ T cells in the skin .

What considerations are important when designing IL17RA truncation or mutation studies?

When investigating IL17RA variants, researchers should consider:

• Functional assessment beyond expression: The novel IL17RA variant p.Tyr391Ter demonstrates that truncated receptors may retain functionality despite missing substantial portions of the protein. Comprehensive functional assessment should include:

  • Protein expression analysis in relevant cell types

  • Membrane localization studies

  • Dimerization capacity with partner receptors

  • Downstream signaling activation

• Tissue-specific effects: The absence of IL17RA in non-hematopoietic versus hematopoietic compartments can lead to different outcomes. Studies should distinguish between these compartments using tissue-specific knockout models or chimeric approaches .

• Compensatory mechanisms: Consider potential compensatory upregulation of other IL17 family receptors or ligands that may mask the direct effects of IL17RA manipulation.

How should researchers approach conflicting data in IL17RA signaling studies?

When confronted with contradictory findings regarding IL17RA function: