Macrophage phosphoproteome analysis reveals MINCLE-dependent and -independent mycobacterial cord factor signaling
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
Originalsprog | Engelsk |
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Tidsskrift | Molecular and Cellular Proteomics |
Vol/bind | 18 |
Udgave nummer | 4 |
Sider (fra-til) | 669-685 |
ISSN | 1535-9476 |
DOI | |
Status | Udgivet - apr. 2019 |
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442366/pdf/zjw669.pdf
Forlagets udgivne version
ID: 211779595