Interleukin 17A (IL-17A) is critical in the host immune response against bacterial and fungal infections, especially at the mucosal surface (1, 2). However, dysregulated IL-17A expression is strongly linked to several human diseases, such as multiple sclerosis (MS), psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and asthma (2). Its biological effects are mediated by activating various signaling pathways that regulate the transcription of target genes involved in inflammation, tissue remodeling, and the recruitment of immune cells (2).

Ubiquitination, a post-translational modification whereby ubiquitin moieties are covalently attached to target proteins, regulates numerous cellular processes, including protein degradation, signal transduction, and cellular localization (3). It involves a multi-enzymatic biochemical reaction in which the Ub-activating (E1) enzyme activates Ub, which is then transferred to the Ub-conjugating (E2) enzyme. The Ub-ligating (E3) enzymes facilitate the formation of the isopeptide bond between the Ub (C-terminus) and specific substrate lysine residues (3). The human genome is estimated to encode 2 E1s, nearly 50 E2s, and over 600 E3s. Each E3 recognizes a set of substrates that share one or more ubiquitination signals, and an individual E3 cooperates with one or a few E2s. The E3 ligases are divided into two different groups based on their functional domains: the homology to the E6-associated protein carboxyl terminus (HECT) type E3s and the fascinating new gene (RING) type E3s (3). The ubiquitin molecules in a polyubiquitin chain are generally linked through the K48 or K63-linked polyubiquitin chains; however, other lysine residues in a ubiquitin molecule have been shown to participate in linkage (3). Interestingly, the different types of polyubiquitin chains have different effects on the substrate. The function of E3 ubiquitin ligases is reversed by the action of deubiquitinating enzymes (DUBs) (4). They specifically cleave the isopeptide bonds between ubiquitin and the Lys residue within the ubiquitinated substrate (4). The dynamic interplay between ubiquitination and the signaling pathways that lead to IL-17 expression is an area of growing interest, offering insights into the fine-tuning of immune responses. Ubiquitin ligases and deubiquitinases modulate the expression of IL-17A and the stability and activity of IL-17A signaling components, thereby influencing the intensity and duration of IL-17A-mediated cellular responses.

Here, we summarize the current knowledge regarding the relationship between IL-17A and ubiquitination, highlighting how this axis regulates immune responses and the implications for therapeutic interventions in inflammatory diseases.

The IL-17 family of cytokines consists of six members (IL-17A to IL-17F) which binds to IL-17 receptors (IL-17RA to IL-17RE) and implement their physiological functions (5). Among the IL-17 family members, IL-17A is the most studied and highly significant cytokine. The human IL-17A is synthesized as a 155-amino-acid precursor which is then posttranscriptional modified by cleave of 23-amino-acid signal peptide at the N-terminus which is followed by dimerization via disulfide bonds to generate mature homodimer of 35 kDa (6). Among the members of the IL-17 family, IL-17F is most similar to IL-17A, with 55% sequence homology (7). IL-17F forms homodimers or heterodimers with IL-17A and binds to IL-17 receptors for signal transduction.

IL-17A is predominantly expressed by CD4⁺ T helper cells (Th17); however, natural killer T cells, CD8⁺ T cells, γδ T cells, innate lymphoid cells (ILCs), dendritic cells, macrophages, and other cells also produce this cytokine (8). The differentiation of Th17 cells depends on the presence of proinflammatory Interleukin-6 (IL-6), Transforming growth factor-beta (TGF-β), and Interleukin 1β (IL-1β) (8, 9). Th17 differentiation requires the activation of the transcription factors signal transducer and activator of transcription 3 (STAT3) and retinoic acid-related orphan receptor gamma t (RORγt) (10). After the initial differentiation, Th17 expresses the IL-23 receptor (IL-23R) and requires IL-23 for their proliferation and survival. Although T-cell receptor (TCR) activation is necessary for CD4⁺ and CD8⁺ T-cell IL-17A synthesis, innate immune cells primarily produce IL-17A in the presence of IL-6 and IL-23 (11).

IL-17A is a potent proinflammatory cytokine that induces neutrophil and monocyte recruitment to the site of inflammation by inducing the expression of chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and CCL20 (8). IL-17A also promotes neutrophil differentiation via the production of granulocyte colony-stimulating factors (G-CSF) and monocyte chemoattractant protein-1 (MCP-1) by non-hematopoietic target cells (11). Il17a deficiencies in mice result in defective neutrophils, leading to increased susceptibility to extracellular pathogens, including the bacteria Klebsiella pneumoniae, Candida albicans, and Toxoplasma gondii (12). In addition, IL-17A regulates the expression of molecules with antimicrobial activity, such as β-defensins, calgranulins, and mucins. Defensins act as natural antibiotics in the lungs, skin, and gut. Another IL-17A target gene is Chemokine (C-C motif) ligand 20 (CCL20), a chemokine that recruits dendritic cells (DCs) and T cells, thereby providing a positive feedback loop for IL-17A amplification by recruiting Th17 cells to inflamed sites (12). However, IL-17A is not always protective against infections. In schistosomiasis, IL-17A stimulates a pathogenic inflammatory response that can be alleviated with antibodies to IL-17A (13). Elevated IL-17A levels are also associated with severe periodontal disease. Importantly, elevated IL-17A is strongly linked to autoimmune pathology. Increased IL-17A levels were found in RA, SLE, and psoriasis patients (11). Consistent results suggest a pathogenic role for IL-17A in various mouse models of autoimmune disease. Similarly, dysregulated IL-17A-mediated inflammation is linked to graft vs host disease and some cancers (14, 15).

The differentiation of Th17 cells requires coordinated activation of T cells in the presence of TGF-β, IL-6, IL-1β, and IL-23 (8). TCR stimulation-induced phosphatidylinositol 3-kinase (PI3K), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Nuclear Factor of Activated T cells (NFAT), and Mitogen-activated protein (MAP) kinase pathways are involved in IL-17A production (10). RAR-related orphan receptor gamma t (RORγt), a member of the nuclear receptor family of proteins, is a key transcriptional factor for IL-17A expression (16). It has been demonstrated that cholesterol derivatives, including desmosterol and oxysterols, serve as natural ligands and activate RORγt (17, 18). Whereas 3-oxoLC, a bile acid synthesized from cholesterol, acts as an inhibitory ligand of RORγt (19). Further, Raftlin1, a lipid raft protein, was shown to recruit specific phospholipids to RORγt and promote the transcriptional activity of RORγt and IL-17A expression (20). RORγt binds to RORE sequences within the CNS2 of the Il17a gene and mediates Il17a transcription by controlling the chromatin remodeling (10). In addition to RORγt, p300 and JmjC domain-containing protein (JMJD)3 also bind to CNS2 and mediate permissive histone acetylation and remove repressive histone marker H3K27me3 (21). CNS2 interacts with the Il17a promoter to induce Il17a transcription (10, 22). Runt-related transcription factor (RUNX)1 also binds to the CNS2 region of Il17a promoter (23). RUNX1 binds to RORgt to enhance expression of Il17a (10, 24).

STAT3 (another transcription factor), activated by IL-6, is involved in IL-17A expression by binding to the the Il17a promoter (25). Additionally, JunB was found to colocalize with interferon regulatory factor (IRF)4, which is involved in IL17A expression (26, 27). IRF4 binds to the regulatory elements of the Il17a promoter, which are co-bound by BATF, an AP-1 factor (10, 27). KLF4, a Kruppel-like factor, is involved in IL-17A expression by directedly binding to the Il17a promoter independently of RORgt (28). A metabolic sensor, Hypoxia-inducible factor (HIF)-1α, associates with RORgt, and binds to hypoxia response element located in the proximal region of the Rorc promoter (29). This suggests a complex network of transcriptional regulators is involved in generating Th17 cells.

Ubiquitin(Ub) conjugation was initially thought to be involved in proteasomal degradation of misfolded proteins (30). However, increasing evidence shows a broader implication in multiple subcellular processes, including the localization of proteins withing the cytoplasm, nuclear translocation, protein-protein interactions, cell membrane receptor turnover, and gene expression. Predictably, IL-17A expression is also regulated by ubiquitin conjugation ( Figure 1 ).

In conclusion, the regulation of IL-17-mediated inflammation by ubiquitination represents a critical layer of control in immune signaling, balancing host defense and the prevention of excessive inflammation. Ubiquitination modulates key components of IL-17A expression and signaling by targeting key signaling intermediates and transcription factors, such as RORγt and STAT3. This post-translational modification fine-tunes the intensity and duration of IL-17-driven responses, thereby shaping the overall immune milieu. Disruptions in this regulatory network are increasingly linked to the pathogenesis of autoimmune diseases, where unchecked IL-17 signaling contributes to chronic inflammation and tissue damage.

Targeting IL-17A and IL-17 receptors using antibodies (e.g., the IL-17 inhibitor secukinumab and the IL-17R inhibitor brodalumab) has achieved remarkable success in treating psoriasis (58). However, these agents have unexpectedly low efficacy in IL-17-related diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). This was suggested to be due to autonomous activation of IL-17R signaling and resistance to IL-17-directed therapy (59). Moreover, there is a potential risk of systemic inactivation of IL-17A activity, which provides host defense and barrier function at mucosal surfaces (60–63). As a result, treatment with IL-17A inhibitors is linked to new-onset and exacerbations of inflammatory bowel disease and colitis (8).

The advancements in the understanding of ubiquitin-mediated regulation could aid in developing strategies to inhibit selective aspects of IL-17A-mediated inflammation in a site-specific manner. Targeted modulation of ubiquitin-related enzymes within the IL-17A pathway holds tremendous promise for the treatment of autoimmune disorders. Small molecules that block or promote interactions between E3 ligases and their substrates could be developed to dampen pathological IL-17 activity without broadly compromising host defense. Moreover, the development of proteolysis-targeting chimeras (PROTACs) presents an exciting avenue for increasing the specificity of substrate degradation, thereby enabling the selective removal of pro-inflammatory signaling proteins. These strategies reflect a shift toward precision immunomodulation, where leveraging the specificity of the ubiquitin system may yield next-generation therapeutics capable of restoring immune balance in autoimmune conditions. Overall, targeting the ubiquitin machinery within the IL-17 axis holds promise for precision immunomodulation, offering opportunities to mitigate chronic inflammation while preserving protective immunity.