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

Lookup NU author(s): Professor Matthias Trost

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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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Abstract

© 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.


Publication metadata

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

Year: 2019

Volume: 18

Issue: 4

Pages: 669-685

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.

URL: https://doi.org/10.1074/mcp.RA118.000929

DOI: 10.1074/mcp.RA118.000929

PubMed id: 30635358


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