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Translational genetics identifies a phosphorylation switch in CARD9 required for innate inflammatory responses.
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.
Afiliação
  • Brandt M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Cao Z; 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 021
  • Krishna C; 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.
  • Reedy JL; Division of Infectious Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Gu X; 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.
  • Dutko RA; Division of Infectious Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Oliver BA; 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.
  • Tusi BK; 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 021
  • Park J; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Richey L; Tufts Comparative Medicine Services, Tufts University, Boston, MA 02111, USA.
  • Segerstolpe Å; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Litwiler S; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Creasey EA; 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.
  • Carey KL; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Vyas JM; Division of Infectious Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Graham DB; 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 021
  • Xavier RJ; 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 021
Cell Rep ; 43(3): 113944, 2024 Mar 26.
Article em En | MEDLINE | ID: mdl-38489265
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Adaptadoras de Sinalização CARD / Micoses Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Adaptadoras de Sinalização CARD / Micoses Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article