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

Research output: Contribution to journalJournal articlepeer-review

  • Madlen Hansen
  • Julien Peltier
  • Barbara Killy
  • Bushra Amin
  • Barbara Bodendorfer
  • Anetta Härtlova
  • Sebastian Uebel
  • Markus Bosmann
  • Jörg Hofmann
  • Christian Büttner
  • Arif B Ekici
  • Mario Kuttke
  • Franzyk, Henrik
  • Foged, Camilla
  • Sandra Beer-Hammer
  • Gernot Schabbauer
  • Matthias Trost
  • Roland Lang

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.

Original languageEnglish
JournalMolecular and Cellular Proteomics
Volume18
Issue number4
Pages (from-to)669-685
ISSN1535-9476
DOIs
Publication statusPublished - Apr 2019

Bibliographical note

Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

ID: 211779595