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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Molecular and Cellular Proteomics
Vol/bind	18
Udgave nummer	4
Sider (fra-til)	669-685
ISSN	1535-9476
DOI	https://doi.org/10.1074/mcp.ra118.000929
Status	Udgivet - apr. 2019

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10.1074/mcp.ra118.000929Licens: CC BY

http://europepmc.org/articles/pmc6442366?pdf=render

Citationsformater

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, bind 18, nr. 4, s. 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",

month = apr,

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

language = "English",

volume = "18",

pages = "669--685",

journal = "Molecular and Cellular Proteomics",

issn = "1535-9476",

publisher = "American Society for Biochemistry and Molecular Biology",

number = "4",

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TY - JOUR

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

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