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

Jung-Lin Wu, Hsin-Yi Wu, Dong-Yan Tsai, Ming-Feng Chiang, Yi-Ju Chen, Shijay Gao, Chun-Cheng Lin, Chun-Hung Lin, Kay-Hooi Khoo, Yu-Ju Chen () and Kuo-I. Lin ()
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Jung-Lin Wu: Institute of Microbiology and Immunology, National Yang-Ming University
Hsin-Yi Wu: Institute of Chemistry, Academia Sinica
Dong-Yan Tsai: Genomics Research Center, Academia Sinica
Ming-Feng Chiang: Genomics Research Center, Academia Sinica
Yi-Ju Chen: Institute of Chemistry, Academia Sinica
Shijay Gao: Institute of Biological Chemistry, Academia Sinica
Chun-Cheng Lin: National Tsing Hua University
Chun-Hung Lin: Institute of Biological Chemistry, Academia Sinica
Kay-Hooi Khoo: Institute of Biological Chemistry, Academia Sinica
Yu-Ju Chen: Institute of Chemistry, Academia Sinica
Kuo-I. Lin: Genomics Research Center, Academia Sinica

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12526

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