The unfolded protein response of B-lymphocytes: PERK-independent development of antibody-secreting cells

Gass, Jennifer N.; Jiang, Hao; Wek, Ronald C.; Brewer, Joseph W.

doi:10.1016/j.molimm.2007.07.029

Cited by 121 publications

(123 citation statements)

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“…The protein folding pathway and the response to ER stress are complex processes with multiple steps. In addition, UPR pathway has been shown to be highly dynamic with distinct kinetic outcomes depending on the input (DuRose et al 2006;Gass et al 2008;Merquiol et al 2011;Pena and Harris, 2011). A mechanistic understanding of this pathway in recombinant cell lines will therefore aid in designing rational metabolic engineering strategies.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of unfolded protein response in recombinant CHO cells

Prashad

Mehra

2014

Cytotechnology

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Genes in the protein secretion pathway have been targeted to increase productivity of monoclonal antibodies in Chinese hamster ovary cells. The results have been highly variable depending on the cell type and the relative amount of recombinant and target proteins. This paper presents a comprehensive study encompassing major components of the protein processing pathway in the endoplasmic reticulum (ER) to elucidate its role in recombinant cells. mRNA profiles of all major ER chaperones and unfolded protein response (UPR) pathway genes are measured at a series of time points in a high-producing cell line under the dynamic environment of a batch culture. An initial increase in IgG heavy chain mRNA levels correlates with an increase in productivity. We observe a parallel increase in the expression levels of majority of chaperones. The chaperone levels continue to increase until the end of the batch culture. In contrast, calreticulin and ERO1-L alpha, two of the lowest expressed genes exhibit transient time profiles, with peak induction on day 3. In response to increased ER stress, both the GCN2/PKR-like ER kinase and inositol-requiring enzyme-1alpha (Ire1a) signalling branch of the UPR are upregulated. Interestingly, spliced X-Box binding protein 1 (XBP1s) transcription factor from Ire1a pathway is detected from the beginning of the batch culture. Comparison with the expression levels in a low producer, show much lower induction at the end of the exponential growth phase. Thus, the unfolded protein response strongly correlates with the magnitude and timing of stress in the course of the batch culture.

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Section: Discussionmentioning

confidence: 99%

Dynamics of unfolded protein response in recombinant CHO cells

Prashad

Mehra

2014

Cytotechnology

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Section: See Accompanying Article By Benhamron Et Almentioning

confidence: 93%

“…At least two additional signaling relays, governed by the ER stress sensors PERK [21] and ATF6 [22,23], operate in parallel to the IRE1-XBP-1 axis in mammals. Yet, only the latter appears to be essential for the ER expansion during B-cell to plasma cell differentiation [24][25][26][27], which nicely illustrates that the mammalian UPR is not a ''monolithic'' response, but rather that individual branches of the UPR may be employed for diverse physiological needs.Meanwhile, using Drosophila as a model, Julie Hollien and Jonathan Weissman asked whether IRE1 or XBP-1 could have distinct targets independent of one another [28]. Indeed, under ER stress conditions, a number of targets were markedly downregulated when XBP-1 was ablated, as compared with ablation of IRE1 alone or of the entire IRE1-XBP-1 relay.…”

mentioning

confidence: 93%

A RIDDle solved: Why an intact IRE1α/XBP‐1 signaling relay is key for humoral immune responses

2014

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To cope with changing environmental conditions, eukaryotic cells employ various stress pathways designed to maintain or restore homeostasis in a given compartment or in response to a particular need. Stress pathways may also be invoked during development, when cells adapt their machineries and reset their homeostatic balances to befit the novel physiological role(s) they are bound to assume. A striking example of this is the differentiation of B cells into antibody-secreting plasma cells. When suitably activated, B cells abandon their quiescent state and undergo an extensive metamorphosis to become -in a matter of few days -one of the most prolific secretory cells [1]. A profound "makeover" is required, that most notably results in a massively expanded endoplasmic reticulum (ER), the organelle where antibodies fold, assemble and are subjected to stringent quality control before proceeding along the exocytic pathway for eventual secretion [1,2].That a signaling pathway is responsible for adjusting the folding capacity of the ER according to necessity was first hypothesized in the late 1980s/early 1990s [3,4], and then proven to indeed exist through genetic screens in yeast [5,6]. Using drugs that perturb productive protein folding specifically in the ER Correspondence: Dr. Eelco van Anken e-mail: eelco.vananken@hsr.it by targeting N-linked glycosylation or disulfide bond formation, the key components of the so-called unfolded protein response (UPR) were identified. Biochemical analyses demonstrated that Ire1 is a transmembrane protein with a stress-sensing domain in the ER and a bifunctional kinase/endonuclease effector domain in the cytosol [7,8]. Intriguingly, the endonuclease domain of Ire1 is dedicated to the excision of an intron from the HAC1 mRNA [7,8]. Upon spliceosome-independent intron removal and religation of the severed exons by Rlg1 [9], the processed HAC1 mRNA encodes a transcription factor that drives the expression of a vast repertoire of chaperones, folding assistants, and other factors needed for the expansion of a functional ER [10].A major breakthrough came when XBP-1 was identified as the mammalian equivalent of yeast HAC1 mRNA, likewise undergoing IRE1α-mediated nonconventional splicing [11][12][13]. Thus, the Ire1/IRE1α-HAC1/XBP-1 axis of the UPR is conserved from yeast to human. These findings, combined with the seminal discovery that XBP-1 is essential for plasma cell differentiation [14], revealed that the IRE1α/XBP-1 relay is central to the development of cells that commit to a professional secretory phenotype [14,15]. Moreover, B-cell activation entails the induction of the transcription factor Blimp-1 [16], which represses BSAP/Pax5 [17,18]. Since BSAP/Pax5 represses XBP-1 [19], the net result is that XBP-1 transcription is enhanced in activated B cells [20]. Altogether,www.eji-journal.eu 642Eelco van Anken et al. Eur. J. Immunol. 2014. 44: 641-645 connecting the dots between the requirements for high antibody production and UPR signaling highlights how findings from fields as di...

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“…When the unfolded protein exceeds a threshold, cell goes to apoptosis (Kim et al, 2006). Three specific stress sensors, IRE1, PERK/PEK and ATF6 serve for ER stress (Gass et al, 2008). We do not have enough data whether there are any connections between these stress sensors and GCs yet.…”

Section: Apoptosis and Protein Traffickingmentioning

confidence: 97%

Glucocortıcoıds: As A Clınıcıan We Use Much, We Know Less

YILDIRAN¹,

DÜZGÜN²,

SANCAK³

2009

jecm

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Glucocorticoids (GC) are frequently used as important drugs in clinical practice of pediatrics. As well as, they have important physiologic functions; they have immune suppressive, antiinflammatory and anti-allergic effects that they exert on primary and secondary immune cells, tissues and organs. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused by the cytosolic glucocorticoid receptor (cGR); secondary non-genomic effects which are also initiated by the cGR; membrane-bound glucocorticoid receptor (mGR)-mediated nongenomic effects and finally non-specific, non-genomic effects caused by interactions with cellular membranes. Mechanisms of GR action are transactivation (GR binds to a related element in the promoter region of GC sensitive genes, inducing gene transcription) and transrepression (GR binds to a negative related element in a promoter region of GCregulated genes that inhibit gene transcription by interfering with the binding of activating transcription factors). The underlying molecular mechanisms for their side effects are complex and frequently partly understood. Recent data suggest that certain side effects are predominantly mediated via transactivation (e.g., diabetes, glaucoma), whereas others are mediated via transrepression (e.g., suppression of the hypothalamic-pituitary-adrenal axis). In this review, we aimed to look at new molecular mechanisms of effects and side effects in relationship with apoptosis and caveolin, intracellular transport and endoplasmic reticulum stress, resistance mechanisms and new drugs developed based on these topics of GCs.

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The unfolded protein response of B-lymphocytes: PERK-independent development of antibody-secreting cells

Cited by 121 publications

References 51 publications

Dynamics of unfolded protein response in recombinant CHO cells

Dynamics of unfolded protein response in recombinant CHO cells

A RIDDle solved: Why an intact IRE1α/XBP‐1 signaling relay is key for humoral immune responses

Glucocortıcoıds: As A Clınıcıan We Use Much, We Know Less

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