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BLNK negatively regulates C-type lectin receptor-mediated antifungal immunity through inhibiting macrophage migration

ABSTRACT: B cell linker protein (BLNK) is a pivotal adaptor protein that interfaces the B cell receptor (BCR)-associated spleen tyrosine kinase (Syk) to regulate B cell function and development. However, it is still not well understood whether BLNK is involved in Syk-coupled C-type lectin receptor (CLR) signaling in myeloid cells, particularly in the context of antifungal immunity. Here, we show that stimulation with fungi-derived β-glucans or α-mannans induced the phosphorylation of BLNK in macrophages, which was significantly impaired due to the deficiency of CLRs including Dectin-1 and Dectin-2, as well as their downstream mediators Syk and Fc-receptor gamma-chain (FcRγ). Furthermore, BLNK is induced to be interacted with casitas B-lineage lymphoma (c-Cbl), which is completely dependent on the engagement of Dectin-1 and Dectin-2. Notably, BLNK deficiency facilitates CLR-mediated recruitment of c-Cbl/phosphatidylinositol 3-kinase (PI3K) complex to F-actin cytoskeleton, thereby promoting macrophage migration. Consequently, mice with monocyte-specific deficiency of BLNK are highly resistant to the infection with Candida albicans, a major human fungal pathogen, through increasing the infiltration of Ly6C+macrophages into kidneys. Together, our data indicate that BLNK functions downstream of Syk-coupled CLRs to negatively regulate antifungal immunity against C. albicans infection. These findings unravel a previously unidentified role of BLNK that negatively regulates macrophage migration through inhibiting CLR-mediated recruitment of c-Cbl/PI3K complex to the cytoskeleton.

ORGANISM(S): Mus musculus

PROVIDER: GSE246891 | GEO | 2023/11/07

REPOSITORIES: GEO

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in vitro ubiquitination by E3 ligase Cbl-b

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