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ERH regulates type II interferon immune signaling through post-transcriptional regulation of JAK2 mRNA

Adrian Soderholm1,2,3, Milica Vunjak1,2,3, Melanie de Almeida3,4

  • 1Max Perutz Labs, Vienna BioCenter Campus (VBC), Dr. -Bohrgasse 9, 1030, Vienna, Austria.

Nucleic Acids Research
|June 30, 2025
PubMed

Insights

Type II interferon (IFNγ) signaling is vital for immunity and cancer therapy. Researchers identified ERH and associated factors that regulate JAK2 mRNA maturation, revealing a new control point for IFNγ responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • Type II interferon (IFNγ) signaling is crucial for innate immunity and cancer immunotherapy.
  • Identifying post-transcriptional regulators of IFNγ signaling is challenging due to essentiality for cell viability.

Purpose of the Study:

  • To screen for key post-transcriptional regulators of IFNγ signaling using an inducible CRISPR/Cas9 system.
  • To elucidate the role of identified factors in JAK2 mRNA maturation and IFNγ pathway regulation.

Main Methods:

  • Utilized an inducible CRISPR/Cas9 genetic screen.
  • Investigated the function of ERH, MAGOH, SRSF1, and ALYREF in IFNγ signaling.
  • Analyzed JAK2 mRNA processing and protein levels.

Main Results:

  • Identified ERH, MAGOH, SRSF1, and ALYREF as critical post-transcriptional regulators of IFNγ signaling.
  • Demonstrated that loss of these factors impairs JAK2 mRNA maturation, reducing JAK2 protein and IFNγ signaling.
  • Discovered ERH's role in preventing intron retention in AU-rich regions of specific transcripts like JAK2.

Conclusions:

  • Post-transcriptional regulation of JAK2 is a rate-limiting step in IFNγ-driven innate immunity.
  • ERH plays a unique role in preventing specific intron retention, impacting immune responses.
  • Findings offer new insights into IFNγ pathway control and potential therapeutic targets in cancer immunotherapy.

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