ISG15 Modulation in Antiviral Immunity and Cancer
Summary
ISG15 is an interferon-stimulated ubiquitin-like protein that exerts pleiotropic effects in innate immunity and tumour biology. Upon type I interferon signalling, ISG15 is rapidly upregulated and can act in two forms: as a free molecule influencing cytokine production and as a covalently attached modifier (ISGylation) that alters the fate and function of target proteins. In antiviral defence, ISG15 conjugation disrupts viral protein assembly or budding, while extracellular ISG15 can stimulate natural killer and T-cell activity. In cancer, the ISG15 system modulates tumour cell death pathways, immune recognition and metabolic adaptation. Regulation of ISG15 conjugation by the de-ISGylase USP18 serves as a critical feedback mechanism. Dysregulation of this axis has been linked to enhanced tumour pyroptosis, immune evasion and altered patient prognosis, highlighting ISG15 as both a biomarker and therapeutic node.
Research from Nature Portfolio
Recent studies have demonstrated that targeted inhibition of USP18 expands the repertoire of interferon-stimulated genes in cancer cells, unleashing a transcriptional programme that promotes pyroptotic cell death and potentiates antitumour immunity. Foundational work comparing human and murine models of ISG15 deficiency revealed that while mice lacking ISG15 display increased viral susceptibility, human cells deficient in ISG15 exhibit enhanced antiviral resistance due to altered feedback control of interferon signalling. Investigations into influenza B virus have uncovered a viral countermeasure whereby the non-structural protein NS1 binds and sequesters ISGylated viral nucleoprotein, preventing its antiviral function and facilitating virus replication.
ISG15 Modulation in Antiviral Immunity and Cancer publication trend
The graph below shows the total number of articles in isg15 modulation in antiviral immunity and cancer across all publications each year (not limited to Nature Index journals).
Technical terms
ISG15: Interferon-stimulated ubiquitin-like modifier induced by type I interferons, existing as a free cytokine or covalent adduct on substrates.
ISGylation: Post-translational conjugation of ISG15 to lysine residues on target proteins, influencing their stability, localisation or interaction networks.
USP18: Ubiquitin-specific protease that removes ISG15 from conjugated proteins and attenuates interferon receptor signalling as a negative regulator.
References
- Expansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis. Nature Communications (2023).
- ISG15 deficiency and increased viral resistance in humans but not mice. Nature Communications (2016).
- Influenza B virus non-structural protein 1 counteracts ISG15 antiviral activity by sequestering ISGylated viral proteins. Nature Communications (2016).
- SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity. Experimental & Molecular Medicine (2024).
- HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis. Journal of Experimental & Clinical Cancer Research (2024).
- ISG15 Inhibits Nedd4 Ubiquitin E3 Activity and Enhances the Innate Antiviral Response*♦. Journal of Biological Chemistry (2008).
- ISG15: leading a double life as a secreted molecule. Experimental & Molecular Medicine (2013).
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