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Temporal regulation of Lsp1 O-GlcNAcylation and phosphorylation duringactivated Bcellsapoptosis

ABSTRACT: Here, we decipher the molecular mechanisms bridging B cell activation and apoptosis mediated by post-translational modification(PTM). We found that O-GlcNAcase inhibition enhances B cell activation and apoptosisinduced by B cell receptor (BCR)cross-linking. This proteome-scale analysis of the functional interplay between protein O-GlcNAcylation and phosphorylation in stimulated mouse primary B cells identified313O-GlcNAcylation-dependent phosphositeson 224 phosphoproteins.Among these phosphoproteins, temporal regulation ofthe O-GlcNAcylation and phosphorylation of lymphocyte-specific protein-1 (Lsp1) is a key switch that triggersapoptosis in activated B cells. O-GlcNAcylation at S209 of Lsp1, identified as the major O-GlcNAc site on Lsp1 by both electron-transfer dissociationand collision-induced dissociationtandem mass spectrometry,was a prerequisite for the recruitment of its kinase, PKC-β1, to induce S243 phosphorylation, leading to ERK activation and down-regulation of BCL-2 and BCL-xL. Thus, we demonstrate the critical PTM interplay of Lsp1 that transmits signals for initiating apoptosis after BCR ligation.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): B Cell

DISEASE(S): Disease Free

SUBMITTER: Hsin-Yi Wu

LAB HEAD: Yu-Ju Chen

PROVIDER: PXD003788 | Pride | 2016-09-26

REPOSITORIES: Pride

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Temporal regulation of Lsp1 O-GlcNAcylation and phosphorylation during apoptosis of activated B cells.

Wu Jung-Lin JL Wu Hsin-Yi HY Tsai Dong-Yan DY Chiang Ming-Feng MF Chen Yi-Ju YJ Gao Shijay S Lin Chun-Cheng CC Lin Chun-Hung CH Khoo Kay-Hooi KH Chen Yu-Ju YJ Lin Kuo-I KI

Nature communications 20160824

Crosslinking of B-cell receptor (BCR) sets off an apoptosis programme, but the underlying pathways remain obscure. Here we decipher the molecular mechanisms bridging B-cell activation and apoptosis mediated by post-translational modification (PTM). We find that O-GlcNAcase inhibition enhances B-cell activation and apoptosis induced by BCR crosslinking. This proteome-scale analysis of the functional interplay between protein O-GlcNAcylation and phosphorylation in stimulated mouse primary B cells ...[more]

PMID: 27555448

Similar Datasets

Project description:Lifestyle and metabolic diseases influence the severity and pathogenesis of cardiovascular disease (CVD) through numerous mechanisms, including regulation via post-translational modifications (PTM). A specific PTM, the addition of O-linked β-N acetylglucosamine (O-GlcNAcylation), has been implicated in both physiological and pathological mechanisms. The current study aimed to test the hypothesis that protein O-GlcNAcylation contributes to cardiac adaptations, and its progression to pathophysiology when sustained in cardiomyocytes. Using an inducible cardiomyocyte-specific dominant-negative O-GlcNAcase (dnOGAh) overexpression transgenic mouse model, we induced dnOGA in 8-10-weeks-old mouse hearts. We examined the effects of 2-weeks (2wk) and 24-weeks (24wk) dnOGA overexpression, which progressed to a 1.8-fold increase in protein O-GlcNAcylation. 2wk increases in protein O-GlcNAc levels did not alter heart weight or function; however, 24wk increases in protein O-GlcNAcylation led to cardiac hypertrophy, reduced mitochondrial function, fibrosis, and diastolic dysfunction. Interestingly, systolic function was maintained in 24wk dnOGA overexpression, despite several changes in gene expression associated with CVD. Specifically, mRNA-seq analysis revealed several gene signatures, including reduction of mitochondrial oxidative phosphorylation, fatty acid and glucose metabolism pathways, and antioxidant response pathways at 24wk. In contrast, cardiac fibrosis pathway genes were induced at 24wk after dnOGA overexpression. Changes in mitochondrial function after 24wk induction were independent of changes in mitochondrial DNA copy number. This study indicates that moderate protein O-GlcNAcylation leads to a differential response with an initial reduction of metabolic pathways (2wk phase), which leads to cardiac remodeling (24wk phase) including cardiac hypertrophy, decreased oxidative phosphorylation pathways, and increased cardiac structural changes. This study shows that sustained exposure of elevated protein O-GlcNAcylation in cardiomyocytes alters gene expression and supports a switch to pathophysiological mechanisms of O-GlcNAcylation in adaptive versus maladaptive changes.

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	B-cell-IPI-mouse_7ppm_p005.dat	Other
	F022814_IgM10m.dat	Other
	F022832_Notreat.dat	Other
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	Igm10min-2.RAW	Raw