Translational Genetics Identifies a Phosphorylation Switch in CARD9 Required for Innate Inflammatory Responses

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2024 Mar 15

PMID 38489265

Authors

Marta Brandt

Zhifang Cao

Chirag Krishna

Jennifer L Reedy

Xiebin Gu

Richard A Dutko

Blayne A Oliver

Betsabeh Khoramian Tusi

Jihye Park

Lauren Richey

Asa Segerstolpe

Scott Litwiler

Elizabeth A Creasey

Kimberly L Carey

Jatin M Vyas

Daniel B Graham

Ramnik J Xavier

Affiliations

Soon will be listed here.

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.

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