Stressed-out B cells? Plasma-cell differentiation and the unfolded protein response

USP19 deubiquitinating enzyme has two isoforms, cytoplasmic and endoplasmic reticulum (ER) localized. The ER-localized isoform specifically suppresses muscle cell differentiation in vitro and appears to do so by inhibiting the unfolded-protein response that occurs during such differentiation. In vivo, loss of USP19 promotes muscle regeneration following injury.

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The Human Plasma Cell Gene Expression Program.

Blood ◽

10.1182/blood.v104.11.3242.3242 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3242-3242

Author(s):

John De Vos ◽

Dirk Hose ◽

Thierry Reme ◽

Hartmut Goldschmidt ◽

Jean-Francois Rossi ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Cell Differentiation ◽

Plasma Cell ◽

Expression Profile ◽

Plasma Cells ◽

Plasma Cell Differentiation ◽

Unfolded Protein ◽

The Mean ◽

Protein Response

Abstract Seven purified peripheral blood memory B-cells (BM), seven in-vitro-generated polyclonal plasmablastic cells (PPC) and seven purified bone marrow mature plasma cells (BMPC) were studied by oligonucleotide microarrays. All samples were obtained from healthy volunteers. The gene expression profiling of these samples was determined with Affymetrix pan genomic U133A + B arrays (44 928 oligonucleotide probesets). We determined that 2313 genes were differentially expressed between these three B cell categories (P 〈 0.01 by a Kruskal-Wallis test and a ratio between two categories 〉 3). These 2313 genes were classified into six categories, according to the expression profile: early plasma cell genes (EPC), late plasma cell genes (LPC), genes lost early during plasma cell differentiation (LEPC), genes lost late during plasma cell differentiation (LLPC), genes upregulated only in plasmablasts (PBO) and genes lost only in plasmablasts (LPBO). As expected, Ig transcripts where essentially classified as EPC. As a corollary, genes involved in protein synthesis or degradation, transmembrane transporters and metabolism genes were overrepresented in EPC genes. Interestingly, genes involved in intercellular communication and extracellular matrix were enriched in LPC, highlighting the fact that mature plasma cells develop tight interactions with the bone marrow environment. Of note, genes involved in cell cycle are upregulated mainly in plasmablasts, whereas antiapoptotic genes are lost in plasmablasts only. Mains genes known to be involved in plasma cell differentiation display an expression profile in agreement with published data, as illustrated for transcription factors in Figure 1, validating this DNA microarray dataset. However most of these 2313 genes have either never been described yet or have no yet been linked to plasma cell differentiation. The description of those genes among our genome whose expression vary most during plasma cell differentiation will be an essential step in understanding the biology of a cell type essential to immune defenses and involved in deadly diseases. Figure 1: Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response. Figure 1:. Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response.

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The LMP1 oncogene of EBV activates PERK and the unfolded protein response to drive its own synthesis

Blood ◽

10.1182/blood-2007-07-100032 ◽

2008 ◽

Vol 111 (4) ◽

pp. 2280-2289 ◽

Cited By ~ 70

Author(s):

Dong Yun Lee ◽

Bill Sugden

Keyword(s):

B Cells ◽

Unfolded Protein Response ◽

Threshold Level ◽

Initiation Factor ◽

Barr Virus ◽

Unfolded Protein ◽

General Protein Synthesis ◽

Epstein Barr ◽

The Unfolded Protein Response ◽

Protein Response

The oncogene latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) without a ligand drives proliferation of EBV-infected B cells. Its levels vary in cells of clonal populations by more than 100-fold, which leads to multiple distinct activities of the oncogene. At intermediate levels it drives proliferation, and at high levels it inhibits general protein synthesis by inducing phosphorylation of eukaryotic initiation factor 2α (eIF2α). We have found that LMP1 activates PERK to induce phosphorylation of eIF2α, which upregulates activating transcription factor 4 (ATF4) expression. ATF4, in turn, transactivates LMP1's own promoter. LMP1 activates not only PERK but also inositol requiring kinase 1 (IRE1) and ATF6, 3 pathways of the unfolded protein response (UPR). Increasing expression levels of LMP1 induced a dose-dependent increase in IRE1 activity, as measured by its “splicing” of XBP-1. These infected B cells secrete immunoglobins independent of the levels of LMP1, indicating that only a threshold level of XBP-1 is required for the secretion. These findings indicate that LMP1's activation of the UPR is a normal event in a continuum of LMP1's expression that leads both to stimulatory and inhibitory functions and regulates the physiology of EBV-infected B cells in multiple, unexpected modes.

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Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin

Blood ◽

10.1182/blood-2008-03-143107 ◽

2008 ◽

Vol 112 (4) ◽

pp. 1223-1230 ◽

Cited By ~ 83

Author(s):

Bei Liu ◽

Zihai Li

Keyword(s):

Endoplasmic Reticulum ◽

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Plasma Cell ◽

Cell Biology ◽

Cell Function ◽

Plasma Cell Differentiation ◽

Unfolded Protein

Abstract Endoplasmic reticulum (ER) unfolded protein response (UPR) plays pivotal roles in both early B-cell development and plasma cell differentiation. As a major ER chaperone to mediate the UPR and a master chaperone for Toll-like receptors (TLRs), HSP90b1 (grp94, gp96) has long been implicated to facilitate the assembly of immunoglobulin. We hereby critically and comprehensively examine the roles of HSP90b1 in B-cell biology in vivo using B-cell–specific HSP90b1-null mice. We found that knockout B cells developed normally. There were no apparent problems with plasma cell differentiation, Ig assembly, class-switching, and Ig production. Strikingly, although both mutant conventional and innatelike B cells failed to compartmentalize properly due to loss of select but not all integrins, HSP90b1 was required for neither germinal center formation nor memory antibody responses in vivo. The only significant defect associated with HSP90b1 ablation in B cells was an attenuated antibody production in the context of TLR stimulation. Thus, our study has resolved the long-standing question regarding HSP90b1 in B-cell biology: HSP90b1 optimizes the function of B cells by chaperoning TLRs and integrins but not immunoglobulin. This study also has important implications in resolving the controversial roles of TLR in B-cell biology.

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