Enhancing Asthma Treatment with Ubiquitin-Proteasome System

The Role of Ubiquitin-Proteasome System in Asthma Pathology

The ubiquitin-proteasome system is integral for regulating protein degradation and cellular homeostasis, influencing various biological processes, including immune responses. Dysregulation of the UPS can lead to aberrant protein accumulation, contributing to the pathophysiology of asthma. Recent research has elucidated how E3 ubiquitin ligases and deubiquitinases affect the inflammatory cascade associated with asthma.

E3 ubiquitin ligases, such as the autocrine motor factor receptor (AMFR) and Midline 1 (MID1), facilitate the ubiquitination of key regulatory proteins, thereby modulating immune cell activation and the production of inflammatory cytokines. For instance, AMFR promotes granulocyte macrophage colony-stimulating factor (GM-CSF) production by targeting Cytokine Inducible SH2-containing protein (CIS) for degradation, ultimately enhancing Th2 cell and eosinophil responses (Deng et al., 2025).

Conversely, deubiquitinases (DUBs) are responsible for removing ubiquitin chains from proteins, thereby stabilizing them and prolonging their activity. The dysregulation of DUBs is linked to various inflammatory diseases, including asthma, indicating their potential as therapeutic targets. By modulating the activity of inflammatory mediators, the UPS can influence the severity and progression of asthma.

E3 Ubiquitin Ligases and Their Impact on Inflammation

E3 ubiquitin ligases play a crucial role in the progression of asthma by influencing the synthesis and release of inflammatory factors. Key E3 ligases involved in asthma pathology include:

• AMFR: Promotes the degradation of CIS, facilitating increased GM-CSF production and enhancing eosinophilic inflammation.
• MID1: Mediates the degradation of Protein Phosphatase 2A (PP2A), inhibiting the secretion of critical inflammatory cytokines like Interleukin-25 (IL-25) and Interleukin-13 (IL-13).
• Parkin: Involved in two pathways; it mediates the degradation of P53 and enhances Nuclear Factor Kappa-light-chain-enhancer (NF-κB) production, promoting inflammatory responses.
• Cbx4: Increases Interleukin-9 (IL-9) secretion through the SUMOylation of Hypoxia-inducible factor alpha (HIF-α).

These E3 ligases represent promising therapeutic targets, as their inhibition could potentially reduce airway inflammation and improve asthma symptoms.

Mechanisms of Deubiquitinases in Asthma Development

Deubiquitinases (DUBs) play a critical role in the regulation of the UPS by reversing ubiquitination. The removal of ubiquitin chains stabilizes proteins that might otherwise be targeted for degradation, leading to prolonged activity of pro-inflammatory mediators. For instance, the DUBs have been implicated in sustaining inflammation by preventing the degradation of proteins involved in the Th2 response.

Recent studies suggest that targeting specific DUBs could offer a novel therapeutic approach to asthma management. By inhibiting DUBs that promote inflammation, it may be possible to restore balance in the immune response and mitigate asthma symptoms.

Relationship Between Gut Microbiome and Asthma Symptoms

Emerging evidence indicates that the gut microbiome significantly influences asthma pathology. The interaction between the gut microbiota and the immune system plays a vital role in the development and exacerbation of asthma. Dysbiosis, or an imbalance in the gut microbiome, has been associated with increased asthma severity and frequency of exacerbations.

Probiotic interventions, particularly those involving extracellular vesicles from specific bacterial strains, can modulate gut microbiome composition and function. For example, recent studies have shown that the administration of extracellular vesicles derived from Limosilactobacillus fermentum can ameliorate atopic dermatitis symptoms by regulating serotonin metabolism and promoting beneficial gut bacteria (Choi et al., 2025).

Innovative Therapeutic Strategies Targeting Ubiquitin-Proteasome System

Given the UPS’s crucial role in inflammation regulation, innovative therapeutic strategies targeting this pathway are being explored. Potential avenues include:

1. Inhibition of E3 Ubiquitin Ligases: Developing inhibitors that can selectively target E3 ligases involved in asthma pathology may reduce inflammation and improve airway function.
2. DUB Modulators: Identifying and developing small molecules to inhibit specific DUBs may help restore normal ubiquitination processes, thus regulating inflammatory responses.
3. Microbiome Modulation: Probiotic treatments that alter gut microbiome composition can synergistically work with UPS-targeted therapies to enhance overall treatment efficacy.

These approaches hold promise for advancing precision medicine in asthma treatment, addressing both the symptoms and underlying pathophysiology of the disease.

FAQ

What is the ubiquitin-proteasome system (UPS)? The UPS is a cellular mechanism responsible for the degradation of misfolded or damaged proteins, regulating various cellular processes, including inflammation.

How do E3 ubiquitin ligases affect asthma? E3 ligases facilitate the ubiquitination of proteins involved in inflammation, thereby influencing immune responses and airway hyperresponsiveness in asthm What role do deubiquitinases (DUBs) play in asthma? DUBs remove ubiquitin from proteins, stabilizing them and prolonging their activity, which can sustain inflammatory responses in asthm How does the gut microbiome relate to asthma symptoms? Dysbiosis in the gut microbiome has been linked to increased asthma severity, while probiotics can help modulate immune responses and improve symptoms.

What are some innovative therapies targeting the UPS for asthma treatment? Potential therapies include targeting E3 ligases and DUBs with small molecule inhibitors and using probiotics to modulate gut microbiota alongside UPS-targeted treatments.

References

1. Deng, S., Ding, L., Qian, Y., & Huang, X. (2025). The Role of Ubiquitin-Proteasome System (UPS) in Asthma Pathology. Journal of Asthma and Allergy. Retrieved from https://doi.org/10.2147/JAA.S490039

2. Choi, H., Kwak, M.-J., Choi, Y., Kang, A. N., Mun, D., Oh, S., & Kim, Y. (2025). Extracellular vesicles of Limosilactobacillus fermentum SLAM216 ameliorate skin symptoms of atopic dermatitis by regulating gut microbiome on serotonin metabolism. Gut Microbes

3. Functions of Lysosomes in Mammalian Female Reproductive System. (2025). Reproductive and Developmental Medicine. Retrieved from https://pubmed.ncbi.nlm.nih.gov/11882109/

4. Kidney Disease and Hematopoietic Stem Cell Transplantation. (2025). Kidney360. Retrieved from https://pubmed.ncbi.nlm.nih.gov/11882261/

5. Genome-wide association study of idiopathic epilepsy in the Italian Spinone dog breed. (2025). PLoS One. Retrieved from https://doi.org/10.1371/journal.pone.0315546