Strategies to Target ISG15 and USP18 Toward Therapeutic Applications.

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• ISG15 is an ubiquitin-like protein involved in ISGylation, crucial for anti-pathogen responses and cellular functions.
• USP18 is the primary protease counteracting ISG15 conjugation and a key negative regulator of interferon signaling.
• Dysregulation of USP18 leads to severe interferonopathies, highlighting its critical role in immune homeostasis.

Purpose of the Study:

• To review existing and conceptual assay systems for targeting ISG15, ISGylation, and USP18.
• To identify modulators of ISG15, ISGylation, USP18 function, and their protein-protein interactions.
• To discuss the translational potential of findings from model organisms for therapeutic strategies.

Main Methods:

• Exploration of various assay systems including mouse models, cell-based assays, and biochemical assays.
• Discussion of chemical probes for targeting ISG15 and USP18 pathways.
• Analysis of protein-protein interactions within the ISG15-USP18 regulatory network.

Main Results:

• ISG15 and USP18 have diverse roles beyond pathogen defense, including protein translation, genome stability, and cancer.
• USP18's dual role as a protease and interferon regulator presents unique therapeutic intervention points.
• Species-specific differences in ISG15 necessitate careful evaluation of translational potential.

Conclusions:

• Targeting the ISG15-USP18 axis offers promising therapeutic avenues for various diseases.
• Development of robust assay systems is essential for identifying effective modulators.
• Translational research, considering inter-species variations, is key for clinical applications.