Macrophage phosphoproteome analysis reveals MINCLE-dependent and-independent mycobacterial cord factor signaling

Hansen M, Peltier J, Killy B, Amin B, Bodendorfer B, HäRtlova A, Uebel S, Bosmann M, Hofmann J, Büttner C, Ekici AB, Kuttke M, Franzyk H, Foged C, Beer-Hammer S, Schabbauer G, Trost M, Lang R (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 18

Pages Range: 669-685

Journal Issue: 4

DOI: 10.1074/mcp.RA118.000929

Abstract

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. PLC, PKC), and was enriched for PKC and GSK3 kinase motifs. MINCLE-dependent activation of the PI3K-AKT-GSK3 pathway contributed to inflammatory gene expression and required the PI3K regulatory subunit p85. Unexpectedly, a substantial fraction of TDM-induced phosphorylation was MINCLE-independent, a finding paralleled by transcriptome data. Bioinformatics analysis of both data sets 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.

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Additional Organisation(s)

Involved external institutions

Newcastle upon Tyne Hospitals NHS Foundation Trust United Kingdom (GB) University of Copenhagen Denmark (DK) Karl Landsteiner Gesellschaft Austria (AT)

How to cite

APA:

Hansen, M., Peltier, J., Killy, B., Amin, B., Bodendorfer, B., HäRtlova, A.,... Lang, R. (2019). Macrophage phosphoproteome analysis reveals MINCLE-dependent and-independent mycobacterial cord factor signaling. Molecular & Cellular Proteomics, 18(4), 669-685. https://dx.doi.org/10.1074/mcp.RA118.000929

MLA:

Hansen, Madlen, et al. "Macrophage phosphoproteome analysis reveals MINCLE-dependent and-independent mycobacterial cord factor signaling." Molecular & Cellular Proteomics 18.4 (2019): 669-685.

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