Efficient IgM assembly and secretion require the plasma cell induced endoplasmic reticulum protein pERp1

Anken, Eelco van; Pena, Florentina; Hafkemeijer, Nicole; Christis, Chantal; Romijn, Edwin P.; Grauschopf, Ulla; Oorschot, Viola; Pertel, Thomas; Engels, Sander; Ora, Ari; Lastun, Viorica; Glockshuber, Rudi; Klumperman, Judith; Heck, Albert J. R.; Luban, Jeremy; Braakman, Ineke

doi:10.1073/pnas.0903036106

Cited by 77 publications

(108 citation statements)

References 32 publications

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“…This decrease in IgM secretion was accounted for by slower assembly kinetics of the subunits. However, it was also shown, pERp1 protein expression is tissue specific with highest level in lymphocyte specific tissues (van Anken et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Evaluating the bottlenecks of recombinant IgM production in mammalian cells

et al. 2014

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Despite the fact, that monoclonal antibodies are the fastest growing group of biopharmaceuticals in development, this is not true for the IgM class, which remains as enigmatic as ever. While more examples of usefulness of IgMs for medical applications are emerging, their recombinant production is still not common. In our study, stable monoclonal IgM producing CHO DG44 and HEK 293 cell lines, expressing two model IgM molecules (IgM-617 and IgM-012) were established. Recombinant cell lines were compared in regard of specific productivity, specific growth rate, maximal achieved antibody titer, gene copy numbers and transcription levels of transgene. IgM-617 cell lines were identified as high while IgM-012 clones were low producers. Although differences in gene copy numbers as well as in transcription levels were observed, they did not seem to be a limitation. Levels of relevant endoplasmic reticulumstress related proteins were analyzed and no indications of unfolded protein response were detected. This could indicate that the difference in the intrinsic protein stability of our model proteins (as was previously observed on purified samples) might cause lower yields of IgM-012. Transcriptomics and/or proteomics follow up studies might be necessary for identification of potential bottlenecks in IgM producing cell lines.

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Section: Discussionmentioning

confidence: 99%

Evaluating the bottlenecks of recombinant IgM production in mammalian cells

et al. 2014

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“…The most down-regulated target, Mzb1, was first identified as a novel gene induced during B to plasma cell differentiation, regulating proper assembly and secretion of mature IgM (26,27). It is highly expressed in marginal zone B cells and regulates intracellular Ca 2ϩ flux upon B cell receptor stimulation (25).…”

Section: Discussionmentioning

confidence: 99%

Transgenic Expression of MicroRNA-185 Causes a Developmental Arrest of T Cells by Targeting Multiple Genes Including Mzb1

Belkaya¹,

Murray²,

Eitson³

et al. 2013

Journal of Biological Chemistry

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Background:MicroRNAs have critical roles in T cell development under normal and stress conditions. Results: Increasing miR-185 levels attenuate T cell development via the targeting of Mzb1, Nfatc3, and Camk4. Conclusion: Elevations in miR-185 impair thymopoiesis at several developmental stages. Significance: miR-185 levels are reduced in 22q11.2 deletion syndrome patients and the identification of its gene targets is clinically informative.

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“…Thus when we had completed our MEDA-7 studies in adipose tissue and obesity and were in the process of preparing this manuscript, two papers reporting a similar transcript and identifying an endoplasmic resident protein named pERp1 in the immune system came to our attention. This entity has been attributed a chaperone function during immunoglobulin assembly [48,49].…”

Section: Discussionmentioning

confidence: 99%

Novel hormone-regulated genes in visceral adipose tissue: cloning and identification of proinflammatory cytokine-like mouse and human MEDA-7: implications for obesity, insulin resistance and the metabolic syndrome

2011

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Aims/hypothesis We sought to characterise novel genes dysregulated by sex hormonal imbalances that induce obesity and metabolic disorder in a setting of oestrogen deficiency and androgen dominance in follicle-stimulating hormone receptor (For [also known as Fshr]) knockout female mice. Methods Transcriptome analysis of mesenteric adipose tissue (MAT) of mutants revealed novel genes. One novel gene named Meda-7 was selected for study. Meda-7 was cloned from mouse and human adipose tissue; its expression, hormonal regulation and function were characterised. Results Mouse Meda-7 is richly expressed in deep visceral adipose tissue and encodes a 22 kDa secreted protein with 71% homology to human mesenteric oestrogen-dependent adipose gene-7 (MEDA-7) protein. Both have six conserved cysteines like many cytokines. In obese patients, MEDA-7 is more abundant in omental than subcutaneous fat. Meda-7 is downregulated in For-knockout female MAT at 5 months (obese state) followed by steep upregulation at 9 months (prediabetic condition) when mutants progress towards the metabolic syndrome. Meda-7 is expressed predominantly in the stromal-vascular cell fraction. In this fraction, M1-proinflammatory macrophages are rich in Meda-7. Meda-7 dysregulation in 5-month-old For-knockout MAT is restored by oestrogen, but treatment has no effect in older mutants. Overabundance of MEDA-7 in HEK-293 cells enhances cell proliferation via p42/44 mitogen-activated protein kinases. Secreted MEDA-7 attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes, while downregulating glucose transporter-4 and upregulating both monocyte chemotactic protein-1 and suppressor of cytokine signalling-3. Downstream activity of the insulin signalling mediator, phospho-AKT, is also downregulated. Conclusions/interpretation MEDA-7 is a hormone-regulated adipokine/proinflammatory cytokine that is implicated in causing chronic inflammation, affecting cellular expansion and blunting insulin response in adipocytes.

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Efficient IgM assembly and secretion require the plasma cell induced endoplasmic reticulum protein pERp1

Cited by 77 publications

References 32 publications

Evaluating the bottlenecks of recombinant IgM production in mammalian cells

Evaluating the bottlenecks of recombinant IgM production in mammalian cells

Transgenic Expression of MicroRNA-185 Causes a Developmental Arrest of T Cells by Targeting Multiple Genes Including Mzb1

Novel hormone-regulated genes in visceral adipose tissue: cloning and identification of proinflammatory cytokine-like mouse and human MEDA-7: implications for obesity, insulin resistance and the metabolic syndrome

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