Details

Autor(en) / Beteiligte

• Brandt, Marta
• Cao, Zhifang
• Krishna, Chirag
• Reedy, Jennifer L.
• Gu, Xiebin
• Dutko, Richard A.
• Oliver, Blayne A.
• Tusi, Betsabeh Khoramian
• Park, Jihye
• Richey, Lauren
• Segerstolpe, Åsa
• Litwiler, Scott
• Creasey, Elizabeth A.
• Carey, Kimberly L.
• Vyas, Jatin M.
• Graham, Daniel B.
• Xavier, Ramnik J.

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2024-03, Vol.43 (3), p.113944-113944, Article 113944

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Population genetics continues to identify genetic variants associated with diseases of the immune system and offers a unique opportunity to discover mechanisms of immune regulation. Multiple genetic variants linked to severe fungal infections and autoimmunity are associated with caspase recruitment domain-containing protein 9 (CARD9). We leverage the CARD9 R101C missense variant to uncover a biochemical mechanism of CARD9 activation essential for antifungal responses. We demonstrate that R101C disrupts a critical signaling switch whereby phosphorylation of S104 releases CARD9 from an autoinhibited state to promote inflammatory responses in myeloid cells. Furthermore, we show that CARD9 R101C exerts dynamic effects on the skin cellular contexture during fungal infection, corrupting inflammatory signaling and cell-cell communication circuits. Card9 R101C mice fail to control dermatophyte infection in the skin, resulting in high fungal burden, yet show minimal signs of inflammation. Together, we demonstrate how translational genetics reveals molecular and cellular mechanisms of innate immune regulation. [Display omitted] •CARD9 R101C missense variant is associated with recurrent fungal infections•R101C disrupts a previously undescribed PKCδ phosphorylation site at S104•pS104 actuates a signaling switch to activate CARD9 and allow BCL10 polymerization•CARD9 R101C mouse model reveals cellular antifungal response networks in skin Brandt et al. employ translational genetics to show that a missense variant linked to fungal immunodeficiency, CARD9 R101C, disrupts a signaling switch mediated by phosphorylation of S104. Disabling this switch impairs inflammatory cytokine programs in myeloid cells, which are amplified by chemokines from fibroblasts and keratinocytes, to promote recruitment of leukocytes.