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

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; Henrik Franzyk; Camilla Foged; Sandra Beer-Hammer; Gernot Schabbauer; Matthias Trost; Roland Lang

doi:10.1074/mcp.ra118.000929

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

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, Henrik Franzyk, Camilla Foged, Sandra Beer-Hammer, Gernot Schabbauer, Matthias Trost, Roland Lang

8 Citations (Scopus)

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.

Original language	English
Journal	Molecular and Cellular Proteomics
Volume	18
Issue number	4
Pages (from-to)	669-685
ISSN	1535-9476
DOIs	https://doi.org/10.1074/mcp.ra118.000929
Publication status	Published - Apr 2019

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Hansen, M., Peltier, J., Killy, B., Amin, B., Bodendorfer, B., Härtlova, A., Uebel, S., Bosmann, M., Hofmann, J., Büttner, C., Ekici, A. B., Kuttke, M., Franzyk, H., Foged, C., Beer-Hammer, S., Schabbauer, G., Trost, M., & Lang, R. (2019). Macrophage phosphoproteome analysis reveals MINCLE-dependent and -independent mycobacterial cord factor signaling. Molecular and Cellular Proteomics, 18(4), 669-685. https://doi.org/10.1074/mcp.ra118.000929

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, 'Macrophage phosphoproteome analysis reveals MINCLE-dependent and -independent mycobacterial cord factor signaling', Molecular and Cellular Proteomics, vol. 18, no. 4, pp. 669-685. https://doi.org/10.1074/mcp.ra118.000929

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title = "Macrophage phosphoproteome analysis reveals MINCLE-dependent and -independent mycobacterial cord factor signaling",

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.",

author = "Madlen Hansen and Julien Peltier and Barbara Killy and Bushra Amin and Barbara Bodendorfer and Anetta H{\"a}rtlova and Sebastian Uebel and Markus Bosmann and J{\"o}rg Hofmann and Christian B{\"u}ttner and Ekici, {Arif B} and Mario Kuttke and Henrik Franzyk and Camilla Foged and Sandra Beer-Hammer and Gernot Schabbauer and Matthias Trost and Roland Lang",

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

year = "2019",

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doi = "10.1074/mcp.ra118.000929",

language = "English",

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T1 - Macrophage phosphoproteome analysis reveals MINCLE-dependent and -independent mycobacterial cord factor signaling

AU - Hansen, Madlen

AU - Peltier, Julien

AU - Killy, Barbara

AU - Amin, Bushra

AU - Bodendorfer, Barbara

AU - Härtlova, Anetta

AU - Uebel, Sebastian

AU - Bosmann, Markus

AU - Hofmann, Jörg

AU - Büttner, Christian

AU - Ekici, Arif B

AU - Kuttke, Mario

AU - Franzyk, Henrik

AU - Foged, Camilla

AU - Beer-Hammer, Sandra

AU - Schabbauer, Gernot

AU - Trost, Matthias

AU - Lang, Roland

N1 - Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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.

U2 - 10.1074/mcp.ra118.000929

DO - 10.1074/mcp.ra118.000929

M3 - Journal article

C2 - 30635358

SN - 1535-9476

VL - 18

SP - 669

EP - 685

JO - Molecular and Cellular Proteomics

JF - Molecular and Cellular Proteomics

IS - 4

ER -

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

Abstract

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