Transcriptional repressor Capicua is a gatekeeper of cell-intrinsic interferon responses.

Summary

An evolutionarily conserved CIC–ATXN1L transcriptional repressor binds an 8‑nt motif near IFN/ISG promoters to prevent inappropriate activation at homeostasis; during respiratory viral infection, MAPK signaling triggers complex degradation, permitting robust IFN/ISG induction. This defines a gatekeeping mechanism that balances antiviral defense and immunopathology.

Key Findings

• CIC–ATXN1L repressor complex binds an 8‑nt motif near IFN and ISG promoters, suppressing baseline inflammatory gene expression in humans and mice.
• Respiratory viral infection activates MAPK signaling, which rapidly degrades CIC–ATXN1L, unleashing robust IFN/ISG induction.
• Defines a conserved homeostatic gatekeeper mechanism for IFN/ISG regulation with therapeutic leverage.

Clinical Implications

Therapeutically modulating MAPK–CIC–ATXN1L could fine‑tune IFN tone: enhancing antiviral responses early in infection or dampening chronic IFN‑driven inflammation in auto-inflammatory conditions.

Limitations

• Downstream clinical translation and safety of tuning IFN via MAPK–CIC modulation remain to be determined.
• Scope across diverse respiratory viruses and tissue contexts warrants further study.

Future Directions

Dissect tissue‑specific CIC–ATXN1L dynamics in human airway/alveolar cells; test small‑molecule modulators to calibrate IFN responses in infection and interferonopathies.