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

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

doi:10.1016/j.celrep.2024.113944

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

Cell Rep. 2024 Mar 26;43(3):113944. doi: 10.1016/j.celrep.2024.113944. Epub 2024 Mar 13.

Authors

Marta Brandt¹, Zhifang Cao², Chirag Krishna³, Jennifer L Reedy⁴, Xiebin Gu⁵, Richard A Dutko⁴, Blayne A Oliver⁵, Betsabeh Khoramian Tusi², Jihye Park¹, Lauren Richey⁶, Åsa Segerstolpe¹, Scott Litwiler⁷, Elizabeth A Creasey⁵, Kimberly L Carey¹, Jatin M Vyas⁴, Daniel B Graham², Ramnik J Xavier⁸

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁴ Division of Infectious Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁶ Tufts Comparative Medicine Services, Tufts University, Boston, MA 02111, USA.
⁷ Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: rxavier@broadinstitute.org.

Abstract

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.

Keywords: CARD9; CP: Immunology; PKCδ; antifungal immune response; cytokine signaling; dermatophytosis.

MeSH terms

Animals
Antifungal Agents
CARD Signaling Adaptor Proteins* / metabolism
Inflammation
Mice
Mycoses*
Phosphorylation
Signal Transduction

Substances

CARD Signaling Adaptor Proteins
Antifungal Agents
Card9 protein, mouse

Abstract

MeSH terms

Substances

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