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Macrophage Phosphoproteome Analysis Reveals MINCLE-dependent and -independent Mycobacterial Cord Factor Signaling.

Journal article
Authors Madlen Hansen
Julian Peltier
Barbara Killy
Bushra Amin
Barbara Bodendorfer
Anetta Härtlova
Sebastian Uebel
Markus Bosmann
Jörg Hofmann
Christian Büttner
Arif B Ekici
Mario Kuttke
Henrik Franzyk
Camilla Foged
Sandra Beer-Hammer
Gernot Schabbauer
Matthias Trost
Roland Lang
Published in Molecular & cellular proteomics : MCP
Volume 18
Issue 4
Pages 669-685
ISSN 1535-9484
Publication year 2019
Published at
Pages 669-685
Language en
Links dx.doi.org/10.1074/mcp.RA118.000929
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords C-type lectin receptor, Kinases, Mincle, Phosphoproteome, RNA SEQ, Signal Transduction, Tuberculosis, macrophage, mycobacteria; trehalose-6, 6-diymcolate
Subject categories Immunology in the medical area, Immunobiology, Cell biology

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. PLCγ, PKCδ), and was enriched for PKCδ and GSK3 kinase motifs. MINCLE-dependent activation of the PI3K-AKT-GSK3 pathway contributed to inflammatory gene expression and required the PI3K regulatory subunit p85α. 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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