Abstract
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 identifies 313 O-GlcNAcylation-dependent phosphosites on 224 phosphoproteins. Among these phosphoproteins, temporal regulation of the O-GlcNAcylation and phosphorylation of lymphocyte-specific protein-1 (Lsp1) is a key switch that triggers apoptosis in activated B cells. O-GlcNAcylation at S209 of Lsp1 is a prerequisite for the recruitment of its kinase, PKC-β1, to induce S243 phosphorylation, leading to ERK activation and downregulation of BCL-2 and BCL-xL. Thus, we demonstrate the critical PTM interplay of Lsp1 that transmits signals for initiating apoptosis after BCR ligation.
Highlights
Crosslinking of B-cell receptor (BCR) sets off an apoptosis programme, but the underlying pathways remain obscure
We show that the inhibition of OGA promotes apoptosis in activated B cells, which is crucially dependent on the O-GlcNAcylation of lymphocyte-specific protein-1 (Lsp1), the recruitment of its kinase, PKC-b1, and the phosphorylation-mediated transduction of apoptotic signals
By monitoring the expression of the activation surface marker CD86, we examined the effects of TG treatment on B-cell activation caused by BCR crosslinking and found that treatment with TG caused modest increases in CD86 expression (Fig. 1d); this result was consistent with a previous work showing that pretreatment with PUGNAc, a less specific OGA inhibitor[13], sensitizes B-cell activation[11]
Summary
Crosslinking of B-cell receptor (BCR) sets off an apoptosis programme, but the underlying pathways remain obscure. 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 identifies 313 O-GlcNAcylation-dependent phosphosites on 224 phosphoproteins. The molecular switch that integrates the apoptotic pathway with BCR activation signalling remains unclear In this regard, we speculated whether the onset of apoptosis following BCR activation could be modulated via crosstalk between posttranslational modifications (PTMs) of critical apoptosis regulators. To identify the molecular switch integrating BCR activation and the apoptosis pathway, we report the proteome-scale dissection of the functional interplay between protein O-GlcNAcylation and phosphorylation dynamics in activated primary B cells. We show that the inhibition of OGA promotes apoptosis in activated B cells, which is crucially dependent on the O-GlcNAcylation of lymphocyte-specific protein-1 (Lsp1), the recruitment of its kinase, PKC-b1, and the phosphorylation-mediated transduction of apoptotic signals
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