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Review
, 41 (8), 705-716

Roles of Endoplasmic Reticulum Stress in Immune Responses

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Review

Roles of Endoplasmic Reticulum Stress in Immune Responses

Jae-Seon So. Mol Cells.

Erratum in

Abstract

The endoplasmic reticulum (ER) is a critical organelle for protein synthesis, folding and modification, and lipid synthesis and calcium storage. Dysregulation of ER functions leads to the accumulation of misfolded- or unfolded-protein in the ER lumen, and this triggers the unfolded protein response (UPR), which restores ER homeostasis. The UPR is characterized by three distinct downstream signaling pathways that promote cell survival or apoptosis depending on the stressor, the intensity and duration of ER stress, and the cell type. Mammalian cells express the UPR transducers IRE1, PERK, and ATF6, which control transcriptional and translational responses to ER stress. Direct links between ER stress and immune responses are also evident, but the mechanisms by which UPR signaling cascades are coordinated with immunity remain unclear. This review discusses recent investigations of the roles of ER stress in immune responses that lead to differentiation, maturation, and cytokine expression in immune cells. Further understanding of how ER stress contributes to the pathogenesis of immune disorders will facilitate the development of novel therapies that target UPR pathways.

Keywords: ER stress; X-box binding protein 1 (XBP1); immune response; inositol requiring enzyme 1 (IRE1); unfolded protein response (UPR).

Figures

Fig. 1
Fig. 1. ER stress and the unfolded protein response (UPR)
The endoplasmic reticulum (ER) is an essential organelle for protein synthesis, folding, and modification. The ER also plays important roles in lipid biosynthesis, calcium storage, and detoxification. ER homeostasis is disturbed by physiological and pharmacological stressors, and the resulting accumulations of misfolded proteins cause ER stress. ER stress triggers the UPR, which is an adaptive cellular response that is mediated by the three mammalian UPR transducers IRE1, PERK, and ATF6. Under conditions of ER stress, these proteins have various signal-mediated transcriptional effects that ameliorate ER stress. Proteins that are induced by IRE1, PERK, and ATF6 are involved in protein folding and ER expansion, and some attenuate protein translation. In addition, the UPR induces ERAD, which mediates degradation of unfolded proteins by proteasome. Under overwhelming conditions of ER stress, the UPR initiates apoptosis. IRE1, inositol-requiring enzyme 1; PERK, protein kinase R-like ER kinase; ATF6, activating transcription factor 6; ERAD, ER-associated degradation.
Fig. 2
Fig. 2. Signaling pathways of the UPR
ER-resident proteins IRE1, PERK, and ATF6 sense ER stress and deliver distinct signals from the ER to the cytosol. Under normal conditions, Grp78 binds to the ER luminal domains of sensor proteins and inhibits their activation. However, Grp78 dissociates from the sensors in response to ER stress and binds to unfolded proteins, leading to activation of the sensors. (A) IRE1 pathway; IRE1 has Ser/Thr kinase and RNase domain in the cytoplasmic region, and ER stress induces IRE1 oligomerization and autophosphorylation of the kinase domain. The RNase domain of activated IRE1 performs unconventional splicing and cleaves 26 intronic nucleotides from XBP1 mRNA in mammalian cells. This splicing induces a translational frame-shift, and the truncated XBP1 mRNA encodes XBP1s, which contains a new carboxyl terminus. As a transcription factor, XBP1s activates UPR-related genes including ER chaperones, ERAD components, and lipid-biosynthetic enzymes. (B) PERK pathway; PERK is a protein Ser/Thr kinase that undergoes oligomerization and autophosphorylation of the kinase domain under conditions of ER stress. Activated PERK phosphorylates eIF2α at serine 51, resulting in general inhibition of protein translation. However, phosphorylated eIF2α selectively increases the translation of ATF4, which upregulates CHOP and GADD34 mRNA. As a negative feedback mechanism, GADD34 promotes dephosphorylation of eIF2α to restore protein synthesis following elimination of ER stress. However, failure to alleviate ER stress leads to CHOP-mediated apoptosis. (C) ATF6 pathway; ATF6 has a bZIP domain in the cytosol and translocates from the ER to the Golgi apparatus under ER stress. ATF6 is then cleaved by the proteases S1P and S2P to produce the aminoterminus of ATF6 (ATF6-N), which then migrates to the nucleus and upregulates target genes encoding ER chaperones, ERAD components, and XBP1. RNase, endoribonuclease; XBP1, X-box binding protein 1; eIF2α, α-subunit of eukaryotic translation initiation factor 2; ATF4, activating transcription factor 4; CHOP, C/EBP homologous protein; GADD34, growth arrest and DNA damage-inducible protein 34; S1P, site-1 protease.
Fig. 3
Fig. 3. Crosstalk between ER stress and inflammatory responses
ER stress-induced signaling pathways play important roles in inflammatory responses. (A) Increased inflammation due to ER stress; ER stress has been implicated in the pathogenesis of inflammatory and autoimmune diseases, such as obesity, diabetes, atherosclerosis, myositis, and inflammatory bowel disease. ER stress induces inflammatory responses by activating UPR transcription factors, such as XBP1s, ATF6, and CREBH. These transcription factors upregulate the pro-inflammatory cytokines IL-1β, TNF-α, and IFN-γ, and the acute phase proteins SAP and CRP. (B) Activation of inflammatory signaling by the UPR; ER stress induces interactions between UPR components and inflammatory signaling cascades. Activated IRE1 interacts with IKK via the adaptor protein TRAF2 and induces NF-κB by initiating proteasomal degradation of IκBα. Phosphorylation of eIF2α inhibits the translation of IκBα and lowers expression levels, thereby activating NF-κB. IRE1 also activates JNK by binding TFAF2 at its cytoplasmic region. Activation of NF-κB and AP-1 by ER stress upregulates inflammatory genes, and is considered a mechanism for inducing inflammatory responses. (C) Activation of the UPR by inflammation; pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, induce ER stress and activate the UPR. LPS also increases the expression of inflammatory cytokines and ER stress-related genes. After inflammatory activation, the UPR causes excessive inflammation and induces apoptosis, thus exacerbating disease conditions. CREBH, cAMP responsive element binding protein H; SAP, serum amyloid P-component; CRP, C-reactive protein; IKK, IκB kinase; TRAF2, TNF-α receptor associated factor 2; IκB, inhibitor of κB; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide.
Fig. 4
Fig. 4. Roles of the UPR in immune cells
(A) Roles of the UPR in secretory cells; the UPR regulates ER expansion and protein secretion, and is therefore essential for development, differentiation, and specialized functions of highly secretory cells, such as pancreatic β cells, exocrine acinar cells, hepatocytes, and salivary gland epithelial cells. (B) Roles of the UPR in immune cells; the UPR plays crucial roles in the development of immune cells, such as plasma cells, DCs, and eosinophils. ER stress also regulates immune cell differentiation, activation, and cytokine expression. In CD4+ T cells, the UPR regulates differentiation to Th2 cells, Th17 cells, and Tregs, and has an important function in TCR-mediated activation. The IRE1–XBP1 pathway is important for differentiation of CD8+ T cells into effector cells. The UPR is also activated during B cell differentiation, and XBP1s is essential for antibody secretion from plasma cells. ER stress strongly influences innate and adaptive immune responses by modulating the production of pro-inflammatory cytokines in B cells, macrophages, and DCs. In macrophages, XBP1s and ATF6 function as positive regulators of inflammatory cytokine expression following TLR stimulation. XBP1s also regulates developmental and inflammatory responses of DCs. However, in DCs of tumor microenvironments, XBP1s induces abnormal lipid accumulation and inhibits anti-tumor immunity. TCR, T cell receptor; Th2, T helper type 2; Tregs, regulatory T cells; TLR, Toll-like receptor.
Fig. 5
Fig. 5. Regulated IRE1-dependent decay (RIDD)
(A) Unconventional splicing of XBP1 mRNA by IRE1; ER stress results in activation of the RNase domain of IRE1 by inducing IRE1 oligomerization and autophosphorylation of kinase domains. The RNase domain of activated IRE1 recognizes two stem-loop structures on XBP1 mRNA and splices motifs with the consensus sequence CUGCAG. The 26-nucleotides intron is cleaved from XBP1 mRNA, and the exons are joined by tRNA ligase to generate spliced XBP1 mRNA encoding XBP1s. (B) Regulated IRE1-dependent decay (RIDD); in addition to XBP1 mRNA, IRE1 recognizes ER-bound mRNAs and promotes their degradation to reduce the protein folding load of ER. This process is known as regulated IRE1-dependent decay (RIDD). IRE1 recognition motifs of RIDD substrates carry the CUGCAG consensus sequence and a secondary structure that is similar to the stem-loop of XBP1 mRNA. XBP1 deficiency induces IRE1 hyperactivation in various cells by as yet unknown mechanisms. RIDD targets various mRNAs to achieve diverse physiological functions, such as reducing plasma lipid levels (Ces1, Angptl3), protecting against drug toxicity (Cyp1a2, Cyp2e1), maintaining ER homeostasis in goblet cells (MUC2), and causing dysfunction of pancreatic β-cells (Ins1, Ins2, PC1, PC2, CPE). RIDD also regulates immune processes, such as antigen presentation by CD8α+ DCs (Itgb2, Tapbp), synthesis of secretory IgM in B cells (μS heavy chain), and cytokine production from iNKT cells (T-bet, Gata-3). Ces1, carboxylesterase 1; Angptl3, angiopoietin-like protein 3; Cyp1a2, cytochrome P450 1A2; Cyp2e1, cytochrome P450 2E1; MUC2, mucin 2; Ins1, insulin 1; Ins2, insulin 2; PC1, prohormone convertase 1; CPE, carboxypeptidase E; Itgb2, integrin subunit beta 2; Tapbp, TAP binding protein; μS, secretory μ chain; iNKT, invariant natural killer T.

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