Macrophage phosphoproteome analysis reveals MINCLE-dependent and -independent mycobacterial cord factor signaling
Research output: Contribution to journal › Journal article › Research › peer-review
Immune sensing of Mycobacterium tuberculosis relies on recognition by macrophages. Mycobacterial cord factor, trehalose-6,6'-dimycolate (TDM), is the most abundant cell wall glycolipid and binds to the C-type lectin receptor (CLR) MINCLE. To explore the kinase signaling linking the TDM-MINCLE interaction to gene expression, we employed quantitative phosphoproteome analysis. TDM caused upregulation of 6.7% and suppressed 3.8% of the 14,000 phospho-sites identified on 3727 proteins. MINCLE-dependent phosphorylation was observed for canonical players of CLR signaling (e.g. PLCg, PKCd), and was enriched for PKCd and GSK3 kinase motifs. MINCLE-dependent activation of the PI3K-AKT-GSK3 pathway contributed to inflammatory gene expression and required the PI3K regulatory subunit p85a. Unexpectedly, a substantial fraction of TDM-induced phosphorylation was MINCLE-independent, a finding paralleled by transcriptome data. Bioinformatics analysis of both datasets concurred in the requirement for MINCLE for innate immune response pathways and processes. In contrast, MINCLE-independent phosphorylation and transcriptome responses were linked to cell cycle regulation. Collectively, our global analyses show substantial reprogramming of macrophages by TDM and reveal a dichotomy of MINCLE-dependent and -independent signaling linked to distinct biological responses.
Original language | English |
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Journal | Molecular and Cellular Proteomics |
Volume | 18 |
Issue number | 4 |
Pages (from-to) | 669-685 |
ISSN | 1535-9476 |
DOIs | |
Publication status | Published - Apr 2019 |
Bibliographical note
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442366/pdf/zjw669.pdf
Final published version
ID: 211779595