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

• 成果类型: Article
• 署名作者: Yang, Yi-Heng; Xie, Ke-Fang; Yang, Shuai; Wang, Huan; Ma, Hui-Hui; Zhou, Min; Wang, Zhong-Wei; Gu, Yebo; Jia, Xin-Ming
• 署名单位: Tongji University; Tongji University; China Pharmaceutical University; Tongji University; Tongji University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12543
• DOI: 10.1073/pnas.2400920121
• 发表日期: 2024-10-22
• 关键词: syk tyrosine kinase; h-ras; activation; inflammation; deficiency; survival; DEFENSE; complex; protein; slp65

摘要

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 beta- glucans or alpha- 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.