IL-17R heterodimeric protein: the core receptor complex for Th17-type inflammatory signal transduction

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This article focuses on the molecular characteristics and signal transduction mechanisms of the IL-17 receptor complex, systematically elaborating the structural classification of IL-17 family ligands and their binding modes with the IL-17RA/IL-17RC heterodimeric receptor, analyzing the unique mechanism by which the IL-17 receptor transduces signals through the ACT1 adaptor molecule rather than the JAK-STAT pathway, and discussing the pathological driving role and targeted therapeutic value of the IL-17R complex in autoimmune diseases such as psoriasis and rheumatoid arthritis.

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IL-17R Heterodimeric Protein: The Core Receptor Complex for Th17-Type Inflammatory Signal Transduction

Summary: This article focuses on the molecular characteristics and signal transduction mechanisms of the IL-17 receptor complex, systematically elaborating on the structural classification of IL-17 family ligands and their binding modes with the IL-17RA/IL-17RC heterodimeric receptor, analyzing the unique mechanism by which the IL-17 receptor transduces signals through the ACT1 adaptor molecule rather than the JAK-STAT pathway, and discussing the pathological driving role and targeted therapeutic value of the IL-17R complex in autoimmune diseases such as psoriasis and rheumatoid arthritis.

I. Molecular Characteristics and Structural Classification of IL-17 Family Ligands.

Interleukin-17 (IL-17) is a family of pro-inflammatory cysteine-knot cytokines. This cytokine family is mainly, but not exclusively, produced by a group of cells called Th17 cells in response to stimulation by IL-23. IL-17 synergizes with TNF and IL-1 to promote inflammation and induces the production of many immune signaling molecules, thereby playing an important immunoregulatory role; among these, the most prominent effect is its involvement in inducing and mediating Th17-type pro-inflammatory responses.

IL-17A protein is the founding member of the IL-17 family, sometimes also directly referred to as IL-17 protein. It shares high homology with the viral IL-17-like protein encoded by the genome of the T-lymphotropic infectious rhabdomyovirus saimiri, but has no homology with other known cytokine families. In addition to IL-17A, the IL-17 family also includes IL-17B, IL-17C, IL-17D, IL-17E (now called IL-25), and IL-17F. All members of the IL-17 family share similar protein structures, among which IL-17A and IL-17F are the most thoroughly studied and are currently the main targets of clinical research. IL-17A and IL-17F have similar biological activities, but exert different activities in regulating inflammation in a context-dependent manner; the two can form homodimers and IL-17A-IL-17F heterodimers.

II. Composition and Ligand Binding Modes of the IL-17R Heterodimeric Receptor.

These dimeric ligands bind to the IL-17 receptor complex, which is composed of IL-17RA and IL-17RC chains. The IL-17R heterodimer is the common receptor platform through which IL-17 family ligands exert their biological functions——IL-17A homodimers, IL-17F homodimers, and IL-17A-IL-17F heterodimers all need to bind to the IL-17RA/IL-17RC complex to initiate downstream signaling. After IL-17A ligand binds to IL-17R, it activates the IL-17 pathway, exacerbating autoimmune diseases such as psoriasis. Therefore, targeted blocking of the binding between IL-17A and IL-17R or its upstream pathway can block the activation of Th17-type pro-inflammatory responses, and thus has important clinical significance. The heterodimeric structure of the receptor complex determines its ligand binding selectivity and signal transduction efficiency, and is the structural basis for the functional specificity of the IL-17 family.

III. Unique Transduction Mechanism of the IL-17R Signaling Pathway.

Unlike other cytokine receptors, cytokine signaling of the IL-17 receptor family is transduced through a unique adaptor molecule, ACT1, rather than the JAK-STAT pathway. The IL-17 receptor signaling pathway is first initiated by the recruitment of ACT1, and ACT1 is also considered an essential molecule for activation of IL-17 receptor signaling. ACT1 was previously considered a negative regulatory primer for BAFF and CD40 signaling. ACT1 has E3 ubiquitin ligase activity; after IL-17 signal transduction, ACT1 rapidly recruits and ubiquitinates TRAF6, which is another E3 ubiquitin ligase. As with other pathways that use TRAF6, IL-17 triggers activation of NF-kB through IkB kinase activation and IkBa degradation.

NF-kB subsequently upregulates the expression of IkB and B-cell lymphoma 3-encoded protein. Bcl3 is a non-canonical member of the NF-kB family, thereby promoting the expression of various IL-17-NF-kB-driven pro-inflammatory genes. IkB is associated with psoriasis both genetically and functionally. Under IL-17A stimulation, ACT1 initiates TRAF6 and, through its E3 ligase function, directs the ubiquitination of TRAF6 to transduce downstream signals. P50/p65 is a major component of the classical NF-kB signal transduction pathway and can lead to the expression of G-CSF as well as CXCL1, CXCL2, and CXCL8.

III. Expanded Mechanisms of IL-17R Signaling in Keratinocytes.

TRAF6 can also promote the activation of the mitogen-activated protein kinase and activator protein 1 pathways as well as the activation of C/EBPβ and 8 transcription factors. In turn, the IL-17-NF-kB signaling pathway induces multiple negative feedback loops that inhibit NF-kB activation, including deubiquitinating enzymes or related factors, including A20, Abin-1, and ubiquitin-specific peptidase 25. This delicate positive and negative feedback regulation ensures moderate activation and timely termination of IL-17 signaling.

IV. Expanded Mechanisms of IL-17R Signaling in Keratinocytes.

In keratinocytes, recent studies have shown that tyrosine kinase-driven pathways participate in IL-17-driven signal transduction. It has been reported that SYK kinase binds to ACT1 and TRAF6, thereby acting upstream of NF-kB and leading to the expression of the CCR6 ligand CCL20. CCR6 is expressed on most Th17-type cells and may drive a feed-forward loop of Th17-driven inflammation. In addition, in T cell receptor and Dectin signaling pathways, CARD family proteins bind to Bcl10 and mucosa-associated lymphoid tissue lymphoma translocation protein 1, promoting NF-kB activation; blocking Malt1 partially inhibits IL-17 and tumor necrosis factor in keratinocytes, but more research is needed. As mentioned earlier, IL-17 also induces proliferative signals in keratinocytes through ACT1, which is one of its major contributing factors in psoriasis and may also explain its role in the pathogenesis of skin tumors. Keratinocyte proliferation is promoted by a non-canonical IL-17-mediated TRAF/ERK activation pathway that promotes tumorigenesis.

V. Pathological Role and Disease Association of IL-17R Signaling in Th17-Type Pro-Inflammatory Responses.

In Th17-type pro-inflammatory responses, IL-17 induces the production of different cytokines (e.g., IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α), chemokines (including IL-8, GRO-α, and MCP-1), and prostaglandins (e.g., PGE2) from multiple cell types (fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages). The induced release of cytokines causes common Th17 responses such as airway remodeling. In addition, current research indicates that IL-17 function is also crucial for the survival of the CD4+ T cell subset known as Th17 cells. Due to these effects, the IL-17 family is associated with many immune/autoimmune-related diseases, including rheumatoid arthritis, asthma, lupus, allograft rejection, antitumor immunity, and in recent years psoriasis and multiple sclerosis. As the common receptor for IL-17 family ligands, the IL-17R heterodimer occupies a pivotal position in signal transduction in the pathological processes of the above diseases.

VI. Conclusion.

In IL-17 signaling pathway research and targeted drug development, high-quality IL-17 ligand proteins are core tools for dissecting their binding mechanisms with the IL-17R complex and evaluating targeted drug activity. IL-17A and IL-17F can form heterodimers, and their binding characteristics with the IL-17RA/IL-17RC receptor differ from those of homodimers, making them an important molecular form for studying the fine regulation of IL-17 signaling. In response to the needs of IL-17 signaling pathway research and drug screening, UniAI provides IL-17A&IL-17F Heterodimer Protein, Mouse. This product is suitable for application scenarios such as binding activity analysis of IL-17A/IL-17F heterodimers with the IL-17RA/IL-17RC receptor complex, mechanistic studies of the IL-17R signaling pathway, in vitro screening and evaluation of antibody drugs targeting IL-17A and IL-17F, and IL-17 functional studies in autoimmune disease models such as psoriasis.

As the common receptor complex for IL-17 family ligands, the IL-17R heterodimer, by virtue of its unique structure composed of IL-17RA and IL-17RC chains, its transduction mechanism that signals through ACT1 rather than the JAK-STAT pathway, and its central pivotal position in Th17-type pro-inflammatory responses, has become a key target in the therapeutic field of autoimmune diseases such as psoriasis and rheumatoid arthritis. From the differential binding of IL-17A/IL-17F homodimers and heterodimers to the receptor complex, to the fine regulation of the ACT1-TRAF6-NF-kB signaling axis, and further to the SYK kinase-dependent expanded pathway in keratinocytes, the IL-17R complex continues to drive the in-depth development of Th17 immunobiology. IL-17A&IL-17F Heterodimer Protein, Mouse provides reliable tool support for mechanistic research on the IL-17 signaling pathway and targeted drug development, and will continue to facilitate innovative exploration in the field of autoimmune disease treatment.

This article is reviewed and published by the technical expert team of UA

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