PXD004164

PXD004164 is an original dataset announced via ProteomeXchange.

Title	Proteomics and network analyses reveals inhibition of Akt-mTOR signaling in CD4+ T cells by Mycobacterium tuberculosis Mannose-capped Lipoarabinomannan
Description	CD4+ T cells have a central role in controlling Mtb infection (1). Despite immune control, Mtb persists by interfering with macrophage and T cell function, allowing for pathogen survival. Our group has demonstrated direct and indirect inhibition of CD4+ T cell activation by different Mtb molecules including lipoproteins LpqH, LprA and LprG, and ManLAM (2-5). ManLAM is an abundant glycolipid in the Mtb cell wall and interferes with TCR signaling by down-regulating phosphorylation of Lck, CD3, ZAP70 and LAT (6). Activation through the TCR-CD3 complex leads to marked changes in the proteome of T cells. Entry into cell cycle, production of cytokines and differentiation from naïve to effector and memory T cell are all reflected in the production and modification of multiple proteins. Mass spectrometry (MS) has been used to characterize TCR complex formation (7-11) and the effect of a range of stressors on the T cell proteome (12-14). Recent advances have overcome technical issues in quantitative MS and allow analysis of the complexity and dynamic range of the cellular proteome (15). To extract biological meaning different bioinformatic tools have been developed for MS based cellular studies (16, 17). In this study we used label-free quantitative MS to characterize the effect of ManLAM on the proteome of activated CD4+ T cells. Approximately 5000 peptides were identified and quantitated from three biological experimental datasets in primary murine CD4+ T cells treated with or without ManLAM and activated with anti-CD3 and anti-CD28 monoclonal antibodies (mAb). Peptides with varying abundance were selected by likelihood ratio based statistical significance by comparing the intensities under different experimental conditions. ManLAM treatment resulted in abundance changes for 149 peptides representing 131 proteins in the activated CD4+ T cell proteome that affected a variety of enriched cluster modules and pathways. Validation experiments confirmed Man LAM induced inhibition of Proliferating Cell Nuclear Antigen (PCNA) that regulates cell cycle progression. Protein-protein interaction (PPI) network analysis revealed a central role for the Akt/mTOR signaling pathway. WB studies revealed decreased phosphorylation of both Akt and mTOR in ManLAM treated CD4+ T cells as well as decreased expression of Otub1, a key molecule regulated by mTOR. Thus disruption of the activated CD4+ T cell proteome by ManLAM-mediated inhibition of proximal TCR signaling is primarily mediated through inhibition of Akt-mTOR signaling.
HostingRepository	PRIDE
AnnounceDate	2018-07-05
AnnouncementXML	Submission_2018-07-05_03:13:32.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD004164
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Kathleen Lundberg
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	Oxidation; Carbamidomethyl
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2016-05-17 05:13:07	ID requested
⏵ 1	2018-07-05 03:13:33	announced

Karim AF, Sande OJ, Tomechko SE, Ding X, Li M, Maxwell S, Ewing RM, Harding CV, Rojas RE, Chance MR, Boom WH, T Cells by Mycobacterium tuberculosis Mannose-Capped Lipoarabinomannan. Proteomics, 17(22):(2017) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: Mycobacterium tuberculosis Mannose-capped Lipoarabinomannan , LC/MS/MS, Label Free Proteomics, Pathway analysis

W. Henry Boom
contact affiliation	1Departments of Medicine & 2Pathology, Case Western Reserve University and University Hospitals Case Medical Center; 3Department of Molecular Biology & Microbiology Case Western Reserve University School of Medicine, Cleveland, Ohio 44106,USA.
contact email	whb@cwru.edu
lab head
Kathleen Lundberg
contact affiliation	Case Western Reserve University
contact email	kathleen.lundberg@case.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD004164
     1. Label: PRIDE project
     2. Name: Proteomics and network analyses reveals inhibition of Akt-mTOR signaling in CD4+ T cells by Mycobacterium tuberculosis Mannose-capped Lipoarabinomannan