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

Wu, Jung-Lin; Wu, Hsin‐Yi; Tsai, Dong-Yan; Chiang, Ming-Feng; Chen, Yi–Ju; Gao, Shijay; Lin, Chun‐Cheng; Lin, Chung-Wei; Khoo, Kay‐Hooi; Chen, Yu-Ju; Lin, Kuo‐I

doi:10.1038/ncomms12526

Cited by 37 publications

(51 citation statements)

References 41 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, phosphorylation is important for Daxx in sensitizing stress-induced apoptosis (17). Similarly, phosphorylation of LSP1 S243 is critical for triggering B lymphocyte apoptosis (18). Interestingly, when we checked the expression levels of proapoptosis (Bim, Bax, Bad) and antiapoptosis (Bcl2, Bcl-xl) proteins (19), no obvious differences were observed between WT (Lck-Cre + ) and cKO (Lck-Cre + Ppp2ca flox/flox ) thymocytes, in either unstimulated cells or cells stimulated with anti-CD3 (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

Zheng

Zhao

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2ca flox/flox -Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4 + CD8 + cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival. thymocyte selection | PP2A | apoptosis T lymphocytes are the major form of adaptive immune cells that target pathogens (1, 2). T cell precursors originate in the bone marrow and then migrate to the thymus to initiate differentiation into mature T cells. In the thymus, CD4 -CD8doublenegative (DN) thymocytes (which can be subcategorized as stages DN1-DN4) acquire T cell receptor (TCR) expression through VDJ recombination and develop into CD4 + CD8 + double-positive (DP) thymocytes, which subsequently give rise to CD4 + or CD8 + single-positive (SP) T cells. Two pivotal selection processes occur, namely positive selection and negative selection, and both serve as gatekeepers in the progress of DP T cells to the SP stage. Notably, only a small percentage of DP thymocytes survive through the selection process to become mature T cells bearing TCRs with suitable reactivity. Secure survival of the T cells which do pass selection is then of pivotal importance during thymic development.It has been shown that TCRs on the DP cell surface can bind to self-peptide-major histocompatibility complex (MHC) complexes on thymic epithelial and dendritic cells, which provide signals for thymocyte survival (3-5). Up-regulation of expression of survival-related proteins is one of the known mechanisms to promote thymocyte survival in this context. Well-studied examples include the Bcl-2 family prosurvival proteins Bcl-xL, whose stage-specific enrichment promotes the survival of DP thymocytes (6). In addition to regulations at the level of gene expression, further studies revealed that posttranslational ...

show abstract

Section: Resultsmentioning

confidence: 99%

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

Zheng

Zhao

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Golks et al [23] showed that induced O-GlcNAcylation of nuclear factor-kappa B (NF-κB) and nuclear factor of activated T cells (NFAT) is required for T-and B-lymphocyte activation. Additionally, the critical interplay between O-GlcNAcylation and phosphorylation for lymphocyte-specific protein-1 (Lsp-1) during B cell activation was proposed as a novel regulatory mechanism to explain how B cells control survival or apoptotic fate after BCR cross-linking [24]. Moreover, genetically engineered mouse models in which Ogt can be deleted at differential stages of B cell development showed not only defective activation of BCR signaling but also significant disruption of B cell homeostasis by enhancing apoptosis of germinal center B cells and memory B cells, which eventually resulted in reduced production of antibodies following immunization [25].…”

Section: Introductionmentioning

confidence: 99%

Increased O-GlcNAcylation of c-Myc Promotes Pre-B Cell Proliferation

Lee

Kwon

Lee

et al. 2020

Cells

View full text Add to dashboard Cite

O-linked β-N-acetylglucosamine (O-GlcNAc) modification regulates the activity of hundreds of nucleocytoplasmic proteins involved in a wide variety of cellular processes, such as gene expression, signaling, and cell growth; however, the mechanism underlying the regulation of B cell development and function by O-GlcNAcylation remains largely unknown. Here, we demonstrate that changes in cellular O-GlcNAc levels significantly affected the growth of pre-B cells, which rapidly proliferate to allow expansion of functional clones that express successfully rearranged heavy chains at the pro-B stage during early B cell development. In our study, the overall O-GlcNAc levels in these proliferative pre-B cells, which are linked to the glucose uptake rate, were highly induced when compared with those in pro-B cells. Thus, pharmacologically, genetically, or nutritionally, inhibition of O-GlcNAcylation in pre-B cells markedly downregulated c-Myc expression, resulting in cell cycle arrest via blockade of cyclin expression. Importantly, the population of B cells after the pro-B cell stage in mouse bone marrow was severely impaired by the administration of an O-GlcNAc inhibitor. These results strongly suggest that O-GlcNAcylation-dependent expression of c-Myc represents a new regulatory component of pre-B cell proliferation, as well as a potential therapeutic target for the treatment of pre-B cell-derived leukemia.

show abstract

“…45 It is not known if Lsp-1 in neutrophils is influenced by O-GlcNAcylation, but this protein, as alluded to before, requires O-GlcNAcylation at serine 209 for serine 243 phosphorylation and subsequent F-actin interactions in murine B cells. 29 A more extensive analysis of overall O-GlcNAcylation levels in human neutrophils by flow cytometry and fluorescence microscopy also showed increased O-GlcNAcylation following fMLP stimulation when compared with unstimulated controls. 46 Although these results indicate that neutrophil chemotaxis is positively dependent on O-GlcNAcylation, there also is a study which found an inhibitory effect of GlcN treatment on human neutrophil chemotaxis and fMLP-driven F-actin interactions.…”

Section: O-glcnacylation In Bacterial Infectionsmentioning

confidence: 90%

“…This binding subsequently results in apoptosis as a consequence of reduced Bcl-2 and Bcl-X L expression. 29 Hence, O-GlcNAcylation is also involved in apoptosis of activated B cells. Lastly, the O-GlcNAcylation of EZH2 may also be of importance in humoral immunity against viral infections.…”

Section: O-glcnacylation In Viral Infectionsmentioning

confidence: 99%

“…O-GlcNAcylation can promote phosphorylation of proteins such as Lsp-1 in B cells, which is required for its interactions with F-actin. 29 Furthermore, O-GlcNAcylation can target proteins for ubiquitination, such as the macrophage proteins MAVS and IRF5, which require ubiquitination for their downstream signaling. [14][15][16] However, this is likely only the tip of the iceberg.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The role of O‐GlcNAcylation in immunity against infections

2020

View full text Add to dashboard Cite

Mounting an effective immune response is crucial for the host to protect itself against invading pathogens. It is now well appreciated that reprogramming of core metabolic pathways in immune cells is a key requirement for their activation and function during infections. The role of several ancillary metabolic pathways in shaping immune cell function is less well understood. One such pathway, for which interest has recently been growing, is the hexosamine biosynthesis pathway (HBP) that generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the donor substrate for a specific form of glycosylation termed O-GlcNAcylation. O-GlcNAc is an intracellular post-translational modification that alters the functional properties of the modified proteins, in particular transcription factors and epigenetic regulators. An increasing number of studies suggest a central role for the HBP and O-GlcNAcylation in dictating immune cell function, including the response to different pathogens. We here discuss the most recent insights regarding O-GlcNAcylation and immunity, and explore whether targeting of O-GlcNAcylation could hold promise as a therapeutic approach to modulate immune responses to infections.

show abstract

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

Cited by 37 publications

References 41 publications

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

Increased O-GlcNAcylation of c-Myc Promotes Pre-B Cell Proliferation

The role of O‐GlcNAcylation in immunity against infections

Contact Info

Product

Resources

About