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Global proteomic profiling of primary macrophages during M. tuberculosis infection identifies TAX1BP1 as a mediator of autophagy targeting

ABSTRACT: We profiled changes in the macrophage proteome during a time-course of primary murine bone marrow-derived macrophages infected with Mycobacterium tuberculosis. We measured changes in global protein abundance, phosphorylation, and ubiquitylation.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow-derived Macrophage, Macrophage

DISEASE(S): Tuberculosis

SUBMITTER: Jonathan Budzik

LAB HEAD: Jeffery Scott Cox

PROVIDER: PXD015361 | Pride | 2020-02-17

REPOSITORIES: Pride

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Dynamic post-translational modification profiling of <i>Mycobacterium tuberculosis</i>-infected primary macrophages.

Budzik Jonathan M JM Swaney Danielle L DL Jimenez-Morales David D Johnson Jeffrey R JR Garelis Nicholas E NE Repasy Teresa T Roberts Allison W AW Popov Lauren M LM Parry Trevor J TJ Pratt Dexter D Ideker Trey T Krogan Nevan J NJ Cox Jeffery S JS

eLife 20200117

Macrophages are highly plastic cells with critical roles in immunity, cancer, and tissue homeostasis, but how these distinct cellular fates are triggered by environmental cues is poorly understood. To uncover how primary murine macrophages respond to bacterial pathogens, we globally assessed changes in post-translational modifications of proteins during infection with <i>Mycobacterium tuberculosis</i>, a notorious intracellular pathogen. We identified hundreds of dynamically regulated phosphoryl ...[more]

PMID: 31951200

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Project description:The cell surface proteome, the surfaceome, is the interface for engaging the extracellular space in normal and cancer cells. Here we apply quantitative proteomics of N-linked glycoproteins to reveal how a collection of some 700 surface proteins is dramatically remodeled in an isogenic breast epithelial cell line stably expressing any of six of the most prominent proliferative oncogenes, including the receptor tyrosine kinases, EGFR and HER2, and downstream signaling partners such as KRAS, BRAF, MEK and AKT. We find that each oncogene has somewhat different surfaceomes but the functions of these proteins are harmonized by common biological themes including up-regulation of nutrient transporters, down-regulation of adhesion molecules and tumor suppressing phosphatases, and alteration in immune modulators. Addition of a potent MEK inhibitor that blocks MAPK signaling brings each oncogene-induced surfaceome back to a common state reflecting their strong dependence on the MAPK pathway to propagate signaling. Using a recently developed glyco-proteomics method of activated ion electron transfer dissociation (AI-ETD) we found massive oncogene-induced changes in 142 N-linked glycans and differential increases in complex hybrid glycans especially for KRAS and HER2 oncogenes. Overall, these studies provide a broad systems level view of how specific driver oncogenes remodel the surface glycoproteome in a cell autologous fashion, and suggest possible surface targets, and combinations thereof, for drug and biomarker discovery.

2020-04-08 | PXD017039 | Pride

The kinase Isr1 negatively regulates hexosamine biosynthesis in S. cerevisiae

Project description:The S. cerevisiae ISR1 gene encodes a putative kinase with no ascribed function. Here, we show that Isr1 acts as a negative regulator of the highly conserved hexosamine biosynthesis pathway (HBP), which converts glucose into uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the carbohydrate precursor to protein glycosylation, GPI-anchor formation and chitin biosynthesis. Overexpression of Isr1 is lethal and, at lower levels, causes sensitivity to tunicamycin and resistance to calcofluor white, implying impaired protein glycosylation and reduced chitin deposition. GFA1 is the first enzyme in the HBP and is conserved from bacteria and yeast to humans. Isr1 lethality is rescued by overexpression of GFA1 or exogenous glucosamine, which bypasses GFA1's essential function. Gfa1 is phosphorylated in an ISR1-dependent fashion and mutation of Isr1-dependent sites ameliorates the lethality associated with Isr1 overexpression. Isr1 contains a phosphodegron that is phosphorylated by Pho85 and subsequently ubiquitinated by the SCF -Cdc4 complex, largely confining Isr1 protein levels to the time of bud emergence. Mutation of this phosphodegron stabilizes Isr1 and recapitulates the overexpression phenotypes. As Pho85 is a cell cycle and nutrient responsive kinase, this tight regulation of Isr1 may serve to dynamically regulate flux through the HBP and modulate how the cell’s energy resources are converted into structural carbohydrates in response to changing cellular needs.

2020-06-07 | PXD018429 | Pride

Proteomics on formalin-fixed and stained laser-capure microdissected human lung sections

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2021-09-08 | PXD014762 | Pride

DEK/NUP214 SILAC interactormics analysis

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2023-07-02 | PXD038808 | Pride

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