Spermidine reduces ISGylation and enhances ISG15-USP18 interaction

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Interferon-stimulated gene 15 (ISG15) conjugation (ISGylation) is crucial for innate immunity, activated by interferons and infections.
• Over 1100 proteins are ISGylated, with ISG15 removed by proteases like USP18, and high ISGylation may impact COVID-19.
• The relationship between nutrients, such as polyamines, and ISGylation is largely unknown.

Purpose of the Study:

• To investigate the effects of polyamines, specifically spermine and spermidine, on ISGylation.
• To explore the potential mechanisms by which these nutrients influence ISGylation pathways.

Main Methods:

• MCF10A and A549 cell lines were treated with interferon-alpha, spermine, or spermidine.
• Protein expression levels and ISGylation status were measured.
• Direct interactions between spermidine, ISG15, and USP18 were analyzed.

Main Results:

• Both spermine and spermidine demonstrated a dose-dependent reduction in ISGylation.
• Spermidine was observed to directly interact with ISG15 and USP18.
• Spermidine enhanced the interaction between ISG15 and USP18, suggesting a mechanism for reduced ISGylation.

Conclusions:

• Polyamines, spermine and spermidine, can significantly reduce ISGylation.
• Spermidine's interaction with ISG15 and USP18 suggests a role in modulating ISGylation-dependent immune responses.
• These findings open avenues for exploring nutritional interventions in ISGylation-related processes.