BLNK negatively regulates innate antifungal immunity through inhibiting c-Cbl-mediated macrophage migration

Proc Natl Acad Sci U S A. 2024 Oct 22;121(43):e2400920121. doi: 10.1073/pnas.2400920121. Epub 2024 Oct 16.

Abstract

B cell linker protein (BLNK) is crucial for orchestrating B cell receptor-associated spleen tyrosine kinase (Syk) signaling. However, the role of BLNK in Syk-coupled C-type lectin receptor (CLR) signaling in macrophages remains unclear. Here, we delineate that CLRs govern the Syk-mediated activation of BLNK, thereby impeding macrophage migration by disrupting podosome ring formation upon stimulation with fungal β-glucans or α-mannans. Mechanistically, BLNK instigates its association with casitas B-lineage lymphoma (c-Cbl), competitively impeding the interaction between c-Cbl and Src-family kinase Fyn. This interference disrupts Fyn-mediated phosphorylation of c-Cbl and subsequent c-Cbl-associated F-actin assembly. Consequently, BLNK deficiency intensifies CLR-mediated recruitment of the c-Cbl/phosphatidylinositol 3-kinase complex to the F-actin cytoskeleton, thereby enhancing macrophage migration. Notably, mice with monocyte-specific BLNK deficiency exhibit heightened resistance to infection with Candida albicans, a prominent human fungal pathogen. This resistance is attributed to the increased infiltration of Ly6C+ macrophages into renal tissue. These findings unveil a previously unrecognized role of BLNK for the negative regulation of macrophage migration through inhibiting CLR-mediated podosome ring formation during fungal infections.

Keywords: B cell linker protein; C-type lectin receptors; antifungal immunity; macrophage migration; negative regulation.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Candida albicans* / immunology
  • Candida albicans* / physiology
  • Candidiasis* / immunology
  • Candidiasis* / metabolism
  • Candidiasis* / microbiology
  • Cell Movement*
  • Immunity, Innate*
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Macrophages* / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation
  • Podosomes / metabolism
  • Proto-Oncogene Proteins c-cbl* / genetics
  • Proto-Oncogene Proteins c-cbl* / metabolism
  • Proto-Oncogene Proteins c-fyn / genetics
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Signal Transduction
  • Syk Kinase* / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cbl protein, mouse
  • Lectins, C-Type
  • Proto-Oncogene Proteins c-cbl
  • Proto-Oncogene Proteins c-fyn
  • Syk Kinase
  • Syk protein, mouse
  • B cell linker protein