Lookup NU author(s): Professor Matthias Trost
This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Society for Biochemistry and Molecular Biology Inc., 2019.
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© 2019 American Society for Biochemistry and Molecular Biology Inc. All Rights Reserved. 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.
Author(s): Hansen M, Peltier J, Killy B, Amin B, Bodendorfer B, HaRtlova A, Uebel S, Bosmann M, Hofmann J, BuTtner C, Ekici AB, Kuttke M, Franzyk H, Foged C, Beer-Hammer S, Schabbauer G, Trost M, Lang R
Publication type: Article
Publication status: Published
Journal: Molecular and Cellular Proteomics
Print publication date: 01/04/2019
Online publication date: 01/04/2019
Acceptance date: 11/01/2019
Date deposited: 24/04/2019
ISSN (print): 1535-9476
ISSN (electronic): 1535-9484
Publisher: American Society for Biochemistry and Molecular Biology Inc.
PubMed id: 30635358
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