STAG2 deficiency induces interferon responses via cGAS-STING pathway and restricts virus infection

Area of Science:

• Molecular Biology
• Immunology
• Virology
• Genetics

Background:

• Cohesin, a nuclear complex, regulates sister chromatid separation during cell division.
• Somatic mutations in cohesin genes are common in various cancers.
• Host factors influencing rotavirus (RV) replication and innate immunity are not fully understood.

Purpose of the Study:

• To identify host factors and innate immune regulators of rotavirus infection using CRISPR-Cas9 screening.
• To investigate the role of the cohesin complex, specifically STAG2, in rotavirus replication and innate immunity.

Main Methods:

• Genome-wide CRISPR-Cas9 screening was employed to identify host dependency factors for rotavirus.
• Cell culture and human intestinal enteroids were used to assess the impact of STAG2 loss on rotavirus replication.
• Mechanistic studies involved analyzing genomic DNA damage, interferon (IFN) expression, and the cGAS-STING pathway.

Main Results:

• Loss of STAG2, a cohesin subunit, conferred resistance to rotavirus replication.
• STAG2 deficiency induced spontaneous genomic DNA damage and robust interferon expression via the cGAS-STING pathway.
• The resulting activation of JAK-STAT signaling and IFN-stimulated genes provided broad protection against viral infections.

Conclusions:

• The cohesin complex plays a previously unrecognized role in maintaining interferon homeostasis.
• STAG2 loss activates innate immunity, conferring resistance to rotavirus and potentially other viruses.
• Targeting the cohesin-innate immunity axis presents novel therapeutic strategies for viral infections.