The ISG Atlas: a loss-of-function analysis characterizes antiviral properties of interferon stimulated genes

  • Nat Commun. 2026 May 8;17(1):4206. doi: 10.1038/s41467-026-72732-x.
Karsten Krey  #  1 ,  Jennifer Risso-Ballester  #  1 ,  Sabri Hamad  1 ,  Susanne Maidl  1 ,  Sara Bilekova  2  3  4 ,  Quirin Emslander  1 ,  Melissa Verin  1  5 ,  Sarah Mundigl  1 ,  Alexandrina Cernat  1 ,  Antonio Piras  1 ,  Valter Bergant  1 ,  Vincent Grass  1 ,  Andreas Pichlmair  6  7  8
Affiliations
  • 1. Institute of Virology, School of Medicine and Health, Technical University of Munich, Munich, Germany.
  • 2. Institute of Diabetes and Regeneration Research (IDR), Helmholtz Diabetes Center, Munich, Germany.
  • 3. German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • 4. Technical University of Munich, School of Medicine, Munich, Germany.
  • 5. Systems Virology, Institute of Virology, Helmholtz Center Munich, Munich, Germany.
  • 6. Institute of Virology, School of Medicine and Health, Technical University of Munich, Munich, Germany. [email protected].
  • 7. Systems Virology, Institute of Virology, Helmholtz Center Munich, Munich, Germany. [email protected].
  • 8. German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany. [email protected].
  • # Contributed equally.
PMID: 42103727 DOI: 10.1038/s41467-026-72732-x
Abstract

The innate immune system requires the activity of interferon-stimulated genes (ISGs) to mount its protective response against viruses. However, the activity of ISGs against viruses varies widely and is orchestrated by the interplay of hundreds of ISGs. Utilizing a time-resolved, arrayed loss-of-function screen, we systematically investigate 285 ISGs for their virus-modulating activity against eight viruses. The quantitated data from the screen results do not necessarily result in similar quantitative biological effects of gene function but indicates virus specificity of many ISGs and pan-proviral activity of some ISGs, such as RNA 2',3'-cyclic phosphate and 5'-OH Ligase (RTCB). Co-depletions of selected candidates identify ISGs with synergistic functions, highlighting particularly strong synergies between ISGs inhibiting entry pathways and ISGs involved in IFN signaling. Among unexplored ISGs, we identify BORCS8, which has a particularly prominent role in modulating SARS-CoV-2 Infection. Mechanistically, BORCS8 mediates the acidification of early endosomes during viral entry, a process known to facilitate the degradation of virus particles. Collectively, this extensive resource reveals specificities of ISGs identified in this screening system and suggests potential strategies for Antiviral treatment options.

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