Translational genetics identifies a phosphorylation switch in CARD9 required for innate inflammatory responses

Area of Science:

• Immunology
• Genetics
• Biochemistry

Background:

• Population genetics identifies genetic variants linked to immune system diseases.
• Caspase recruitment domain-containing protein 9 (CARD9) is associated with fungal infections and autoimmunity.
• Understanding CARD9's role is crucial for immune regulation mechanisms.

Purpose of the Study:

• To uncover the biochemical mechanism of CARD9 activation using the R101C missense variant.
• To investigate how CARD9 variants affect innate immune responses, particularly in fungal infections.
• To elucidate the molecular and cellular consequences of CARD9 dysfunction in the skin.

Main Methods:

• Utilized the CARD9 R101C missense variant for biochemical analysis.
• Investigated the role of S104 phosphorylation in CARD9 activation and inflammatory signaling.
• Examined the effects of CARD9 R101C on skin cellular contexture and immune cell communication in a fungal infection model.
• Analyzed fungal burden and inflammatory responses in CARD9 R101C mice.

Main Results:

• The R101C variant disrupts a signaling switch, preventing CARD9 autoinhibition release via S104 phosphorylation.
• CARD9 R101C impairs inflammatory responses in myeloid cells, crucial for antifungal defense.
• CARD9 R101C alters skin cellular contexture, corrupting inflammatory signaling and cell-cell communication during fungal infection.
• CARD9 R101C mice exhibit high fungal burden with minimal inflammation, indicating a failure to control dermatophyte infection.

Conclusions:

• Translational genetics provides insights into molecular and cellular mechanisms of innate immune regulation.
• The study reveals a specific biochemical pathway for CARD9 activation essential for antifungal immunity.
• CARD9 dysfunction can lead to uncontrolled fungal infections with aberrant inflammatory responses.