Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1

Iwakoshi, Neal N.; Lee, Ann–Hwee; Vallabhajosyula, Prasanth; Otipoby, Kevin L.; Rajewsky, Klaus; Glimcher, Laurie H.

doi:10.1038/ni907

Cited by 772 publications

(795 citation statements)

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“…Human XBP-1 stealth-select siRNA (HS111392) and low-GC siRNA control were purchased from Invitrogen. The pcDNA3.1 vector containing XBP-1s was provided by L. Glimcher [19]. Plasmids were prepared endotoxin-free (Qiagen) and determined to have <0.1 endotoxin U/mL by Limulus assay (Cambrex).…”

Section: Bone Marrow-derived Macrophagesmentioning

confidence: 99%

“…XBP-1 influences the production of IL-6 in plasma cells, a process that can be initiated by LPS or CD40 ligation [19]. Cholesterol loading of macrophages activates the UPR and induces TNF-a and IL-6 via effects on NF-jB, JNK1/2, p38, and ERK1/2 activation, with the last pathway dependent on UPRinduced C/EBP homologous protein 10 [21].…”

Section: Introductionmentioning

confidence: 99%

“…As an integral part of the UPR, XBP-1 is responsible for up-regulation of a subset of UPR target genes, including several involved in ERAD [18]. In B cells XBP-1 mRNA splicing is triggered by increased Ig synthesis, which results in differentiation into plasma cells with expansion of the ER compartment, thus enabling production and secretion of large amounts of Ig [19]. XBP-1 also has a posttranslational role in sustaining IgM synthesis in B cells [20].…”

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confidence: 99%

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Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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Type I IFN are strongly induced upon engagement of certain pattern recognition receptors by microbial products, and play key roles in regulating innate and adaptive immunity. It has become apparent that the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), in addition to restoring ER homeostasis, also influences the expression of certain inflammatory cytokines. However, the extent to which UPR signaling regulates type I IFN remains unclear. Here we show that cells undergoing a UPR respond to TLR4 and TLR3 ligands, and intracellular dsRNA, with log-fold greater IFN-b induction. This synergy is not dependent on autocrine type I IFN signaling, but unexpectedly requires the UPR transcription factor X-box binding protein 1 (XBP-1). Synergistic IFN-b induction also occurs in HLA-B27/human b 2 m-transgenic rat macrophages exhibiting a UPR as a consequence of HLA-B27 up-regulation, where it correlates with activation of XBP-1 splicing. Together these findings indicate that the cellular response to endogenous 'danger' that disrupts ER homeostasis is coupled to IFN-b induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR.Key words: HLA-B27 Á Interferons Á Protein misfolding Á Unfolded protein response IntroductionInitially identified as antiviral cytokines, type I IFN (IFN-a/b) are now recognized to have diverse immunoregulatory effects activating macrophages and NK cells, promoting T cell survival and dendritic cell (DC) maturation, and increasing the production of Th1-polarizing cytokines to mediate innate and adaptive immune responses [1]. Type I IFN also exert biological effects at low and even constitutive levels of expression [2]. For example, weak IFN-b-mediated signaling augments IFN-a/b induction in response to LPS through positive feedback involving autocrine/ paracrine up-regulation of IFN regulatory factor (IRF)7. In addition, low levels of IFN-a/b prime cells to respond to IFN-c and IL-6 by providing a phosphorylated type I IFN receptor 'niche' for commonly used signaling molecules in proximity to other cytokine receptor complexes [3,4]. Mice deficient in IFN-b are more susceptible to viral infection, have lower numbers of macrophages and mature B cells, and exhibit reduced bone mass [5], as IFN-b is a positive regulator of bone formation through inhibition of osteoclast differentiation [6]. Thus, even constitutive levels of this cytokine are important in osteo-immune homeostasis.IFN-b is produced by most cell types upon viral infection, and in large amounts by macrophages and DC, following engagement of pattern recognition receptors (PRR) by conserved molecular structures referred to as pathogen-associated molecular patterns [7, 8]. PRR that mediate IFN-b induction include cell surface TLR4 and endosomal TLR3 for LPS and dsRNA, respectively [9]. In both instances increased IFN-b gene transcription occurs via TLR/IL-1R domain-containing adapter inducing IFN-b (TRIF)-dependent IRF3 and NF-jB activation. PRR in the retinoic ...

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Section: Bone Marrow-derived Macrophagesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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“…This developmental ER stress is a natural consequence of the transition from B cell to plasma cell, which produces huge amounts of antibodies and requires a massive expansion in ER folding capacity (Iwakoshi et al, 2003).…”

Section: The Monocytementioning

confidence: 99%

“…The spliced form of XBP-1 has been shown to control the production of IL-6 in the mouse B cell (Iwakoshi et al, 2003). XBP-1 was also shown to regulate the production of IFN-β in mouse macrophages subjected to ER stress (Smith et al, 2008).…”

Section: Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

Measurement of the Unfolded Protein Response (UPR) in Monocytes

Carroll¹,

Greene²,

McElvaney³

2011

Methods in Enzymology

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Probing Endoplasmic Reticulum Dynamics using Fluorescence Imaging and Photobleaching Techniques

Costantini

Snapp

2013

CP Cell Biology

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This unit describes approaches and tools for studying the dynamics and organization of endoplasmic reticulum (ER) membranes and proteins in living cells using fluorescence microscopy. The ER plays a key role in secretory protein biogenesis, calcium regulation, and lipid synthesis. However, study of these processes has often been restricted to biochemical assays that average millions of lysed cells or imaging of static fixed cells. With new fluorescent protein (FP) reporter tools, sensitive commercial microscopes, and photobleaching techniques, investigators can interrogate the behaviors of ER proteins, membranes, and stress pathways in single live cells. Solutions are described for imaging challenges relevant to the ER, including the mobility of ER membranes, a range of ER structures, and the influence of post-translational modifications on FP reporters. Considerations for performing photobleaching assays for ER proteins are discussed. Finally, reporters and drugs for studying misfolded secretory protein stress and the unfolded protein response are described.

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Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1

Cited by 772 publications

References 53 publications

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Measurement of the Unfolded Protein Response (UPR) in Monocytes

Probing Endoplasmic Reticulum Dynamics using Fluorescence Imaging and Photobleaching Techniques

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