From:  Protein ISGylation: a posttranslational modification with implications for malignant neoplasms

Effects of free ISG15 that may be relevant in a cancer context

EffectDescription of free ISG15-associated effectsReference
Regulation of IFN signaling

In humans, JAK1-IFNAR2 interaction is disrupted by USP18, affecting IFN-α/β signaling

Free ISG15 interacts with USP18, inhibiting its degradation by SKP2

[67]
Protein complex disassemblyIntracellular free ISG15 interrupts the USP18-SKP2 interaction promoting the stability of USP18[68]
Regulation of E3-ubiquitin ligase activityFree ISG15 binds to the E3-ubiquitin ligase NEDD4 to interrupt its interaction with the E2 biquitin-conjugating enzyme, decreasing ubiquitination[69]
Participation in selective autophagy LRRC25 inhibits the IFN-signaling by promoting lysosomal degradation of ISG15-associated RIG-1[70]
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JAK1-IFNAR2: janus kinase 1-IFN α and β receptor subunit 2; SKP2: S-phase kinase-associated protein 2; NEDD4: NEDD4 E3 ubiquitin protein ligase (also known as NEDD4-1 or RPF1, neural precursor cell expressed, developmentally down-regulated 4); LRRC25: leucine-rich repeat containing 25; RIG-1: RNA sensor RIG-1