ISGS

Interferon-stimulated genes (ISGs) are a broad group of genes whose transcription is upregulated in response to interferon signaling, particularly type I (IFN-α/β) and type II (IFN-γ) interferons. ISGs encode proteins that help establish an antiviral state, regulate immune signaling, and influence cell survival and metabolism.

ISG induction is dominated by the JAK-STAT signaling pathway. Type I interferons binding to IFNAR receptors activate JAK kinases and recruit STAT1/STAT2 and IRF9 to form the ISGF3 complex, which moves to the nucleus and binds interferon-stimulated response elements (ISREs) in target gene promoters. Type II interferon signaling primarily activates STAT1 homodimers that bind gamma-activated sequence (GAS) elements. Many ISGs respond to both pathways, and expression levels vary by cell type, stimuli, and timing. Epigenetic state and additional transcription factors also shape the ISG response.

Common examples of ISGs and their antiviral roles include MX1 and MX2, which block viral replication; OAS1, OAS2, and RNase L, which degrade viral RNA; PKR (EIF2AK2), which inhibits protein synthesis; ISG15, a ubiquitin-like modifier; IFIT family proteins that interfere with viral RNA sensing and translation; and viperin (RSAD2), which disrupts lipid processes essential for some viruses. Together, ISGs execute diverse defense mechanisms such as RNA degradation, translation inhibition, particle assembly interference, and enhancement of antigen presentation.

Clinically, ISG expression underlies the effectiveness of interferon therapies and serves as a biomarker for antiviral responses. Dysregulation of ISGs is linked to autoinflammatory conditions, chronic infections, and influences tumor-immune interactions, making them a focus of basic and translational research.