Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Jun 6:9:1289.
doi: 10.3389/fimmu.2018.01289. eCollection 2018.

IRE1α Implications in Endoplasmic Reticulum Stress-Mediated Development and Pathogenesis of Autoimmune Diseases

Raghu Patil Junjappa  1 , Prakash Patil  1 , Kashi Raj Bhattarai  1 , Hyung-Ryong Kim  2 , Han-Jung Chae  1
Affiliations
Review

IRE1α Implications in Endoplasmic Reticulum Stress-Mediated Development and Pathogenesis of Autoimmune Diseases

Raghu Patil Junjappa et al. Front Immunol. .

Abstract

Inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) is the most prominent and evolutionarily conserved endoplasmic reticulum (ER) membrane protein. This transduces the signal of misfolded protein accumulation in the ER, named as ER stress, to the nucleus as "unfolded protein response (UPR)." The ER stress-mediated IRE1α signaling pathway arbitrates the yin and yang of cell life. IRE1α has been implicated in several physiological as well as pathological conditions, including immune disorders. Autoimmune diseases are caused by abnormal immune responses that develop due to genetic mutations and several environmental factors, including infections and chemicals. These factors dysregulate the cell immune reactions, such as cytokine secretion, antigen presentation, and autoantigen generation. However, the mechanisms involved, in which these factors induce the onset of autoimmune diseases, are remaining unknown. Considering that these environmental factors also induce the UPR, which is expected to have significant role in secretory cells and immune cells. The role of the major UPR molecule, IRE1α, in causing immune responses is well identified, but its role in inducing autoimmunity and the pathogenesis of autoimmune diseases has not been clearly elucidated. Hence, a better understanding of the role of IRE1α and its regulatory mechanisms in causing autoimmune diseases could help to identify and develop the appropriate therapeutic strategies. In this review, we mainly center the discussion on the molecular mechanisms of IRE1α in the pathophysiology of autoimmune diseases.

Keywords: IRE1α; autoimmune diseases; cytokines; inflammation; regulated IRE1α-dependent decay; unfolded protein response signaling pathways.

PubMed Disclaimer

Figures

Figure 1
Figure 1
IRE1α structure and its downstream mechanisms in mild and severe stress. (A) A model depicting the IRE1α structure and its functional domains: luminal domain (LD), transmembrane domain (TD), linker region (LR), kinase domain (KD), RNase domain (RD), and an activation loop at the KD. (B) Stress factors, such as mutations, high demand for secretory proteins, ionic imbalance, and disease cause an accumulation of misfolded proteins, leading to activation of the unfolded protein response. Immunoglobulin binding protein regulates IRE1α through dimerization, autophosphorylation, and further oligomerization. During mild endoplasmic reticulum (ER) stress, activated IRE1α helps the cells to recover from stress through increasing the ER folding chaperones and ER-associated degradation (ERAD) components by generating stable transcription factor XBP1s, as follows: active IRE1α cleaves XBP1 mRNA, and the cleaved fragments are ligated by RtcB. Stable XBP1 mRNA is generated and translated to form the transcription factor XBP1s, which moves to the nucleus and induces the expression of chaperone proteins and ERAD process-associated genes. Another process, regulated IRE1α-dependent decay (RIDD), degrades mRNAs and reduces the load of new proteins entering ER, which helps in cell survival; in addition, the generation of small RNA fragments triggers the inflammatory response. (C) With severe stress, IRE1α induces the alternative pathway: apoptotic signaling by recruiting TNF receptor-associated factor 2 (TRAF2) and apoptosis signaling kinase1, leading to c-Jun N-terminal kinase (JNK) phosphorylation. Phosphorylated JNK induces apoptosis through many signaling pathways. It causes the proapoptotic proteins Bcl-2-associated X protein (BaX), and Bim to translocate to the mitochondrial membrane by inhibiting antiapoptotic B-cell lymphoma family 2 (Bcl-2). The mitochondrial membrane is ruptured, and cytochrome C is released, which activates caspase-9 and -3, which in turn cleave many proteins and cause cell death. Phosphorylated JNK also translocates Sab protein, which increases the mitochondrial reactive oxygen species (ROS) and leads to cell death directly, as well as ROS inducing inflammation-mediated cell death. In addition, JNK-mediated transcription factor AP-1 induces pro-inflammatory cytokine-mediated cell death. IRE1α also can induce inflammation-mediated cell death by activating NFκB. Furthermore, RIDD activity, which degrades prosurvival mRNAs, which increases caspase-2 expression, causes translocation of BH3-interacting domain to the mitochondria, and also degrades miRNA17, which stabilizes the thioredoxin-interacting protein thioredoxin-interacting protein, leading to inflammation and ROS-mediated cell death. In addition, spliced XBP1s stimulates the expression of the proapoptotic protein CCAAT-enhancer-binding protein homologous protein (CHOP), which induces cell death. Finally, IRE1α/TRAF2 association can activate caspase-12-mediated cell apoptosis.
Figure 2
Figure 2
IRE1α regulates the immune function through various mechanisms including both its kinase (A) and RNase (B) functions. (A) Endoplasmic reticulum (ER) stress-activated, serine/threonine-protein kinase/endoribonuclease IRE1α binds to TNF receptor-associated factor 2 (TRAF2), apoptosis signaling kinase1 (ASK1), and receptor-interacting serine/threonine protein kinase 1 (RIPK1), resulting in phosphorylation of c-Jun N-terminal kinase. Then c-Jun interacts with c-Fos forms the active transcription factor AP-1, and increases the production of IL-6 and TNFα. Furthermore, the IRE1α/TRAF2/ASK1 complex activates the inhibitory kappa B kinase (IKK), which phosphorylates inhibitor of kappa B (IκB), leading to release of NFκB and its translocation to the nucleus, where it induces the expression of cytokines. The dissociated IκB is then degraded by proteasomes. The IRE1α–TRAF2 complex increases IL-6 production via the association of nucleotide-binding oligomerization domain (NOD)-containing proteins 1 and 2 (NOD1 and NOD2) and receptor-interacting serine/threonine-protein kinase 2 (RIPK2). (B) IRE1α through its RNase function generates splices—X-box-binding protein 1 (XBP1s) transcription factor induces the expression of several pro-inflammatory cytokines and also decreases MHC class I antigen presentation. In addition, XBP1s increases NFκB nuclear translocation by mediating the degradation of FoxO1, an inhibitor of NFκB. Furthermore, IRE1α activation differentially regulates the expression of the pro-inflammatory cytokine IL-1β gene via activation of glycogen synthase kinase-3β. The regulated IRE1α-dependent decay (RIDD) degrades miR-17, leading to an increase in thioredoxin-interacting protein expression. This in turn activates nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activity, which leads to procaspase-1 cleavage, which subsequently activates IL-1β, IL-18, and IFN-β, and also increases the Th-cell 1 immune response. RIDD generates small fragments of RNA, which activate the retinoic inducible gene-I and mitochondrial antiviral protein, increasing IFNβ production via NFκB. In addition, RIDD reduces the TAPBP mRNA level, leading to decreased antigen presentation. Toll-like receptors 2, 4, and 7 and other cytokines can directly activate the IRE1α/XBP1s pathway without ER stress and cause the release of many pro-inflammatory cytokines.
Figure 3
Figure 3
Potential mechanisms of IRE1α in the development of autoimmune diseases. IRE1α activation by environmental factors or gene mutations that induce endoplasmic reticulum (ER) stress can lead to autoimmune disease development through various pathways. Spliced XBP1s increases the expression of the microRNA miR-346, which binds to the 3′-UTR of transporter associated with antigen processing (TAP) mRNA, leading to TAP mRNA decay. This reduces MHC class I complex formation and antigen presentation. XBP1s increases the expression of ER degradation-enhancing α-mannosidase-like protein and homocysteine-induced ER protein, leading to enhanced ER-associated degradation (ERAD), which can lead to autoimmune disease by increasing immune cell survival especially that of fibroblast-like synoviocytes. Misfolded proteins may act as autoantigens; for example, human leukocyte antigen B27 (HLA-B27), immunoglobulin binding protein (BiP), and pro-insulin. IRE1α has a role in the increased expression of BiP, and pro-insulin during stress and these proteins may act as autoantigens/neoantigens. IRE1α activation during the response to misfolded HLA-B27 misfolded response may contribute to autoimmunity in ankylosing spondylitis. ER stress or toll-like receptor-activated IRE1α mediates the production of pro-inflammatory cytokines through c-Jun N-terminal kinase, such as NFκB, XBP1s, and regulated IRE1α-dependent decay (RIDD), which increases the pathogenesis in autoimmune diseases. RIDD activity reduces MHC class I antigen presentation by reducing TAPBP protein synthesis. In addition, RIDD-mediated activation of nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 inflammasomes leads to increased secretion of IL-1β and IL-18, which increase the T-helper-1 cell immune response, which is characteristic of many autoimmune diseases. Furthermore, through inhibition of IRE1α, either with small chemical molecules, such as 8-formyl-7-hydroxy-4-methylcoumarin (4μ8c), sunitinib, imatinib, or by enhancing expression of negative regulators of IRE1α such as fortilin, it may be possible to reduce the progression of autoimmune diseases.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Liang Y, Meng FY, Pan HF, Ye DQ. A literature review on the patients with autoimmune diseases following vaccination against infections. Hum Vaccin Immunother (2015) 11(9):2274–80.10.1080/21645515.2015.1009337 - DOI - PMC - PubMed
    1. Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med (2015) 278(4):369–95.10.1111/joim.12395 - DOI - PubMed
    1. Coronel-Restrepo N, Posso-Osorio I, Naranjo-Escobar J, Tobon GJ. Autoimmune diseases and their relation with immunological, neurological and endocrinological axes. Autoimmun Rev (2017) 16(7):684–92.10.1016/j.autrev.2017.05.002 - DOI - PubMed
    1. Savioli B, Abdulahad WH, Brouwer E, Kallenberg CGM, de Souza AWS. Are cytokines and chemokines suitable biomarkers for Takayasu arteritis? Autoimmun Rev (2017) 16(10):1071–8.10.1016/j.autrev.2017.07.023 - DOI - PubMed
    1. Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA, Selmi C, et al. Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun (2012) 38(2–3):J156–69.10.1016/j.jaut.2011.11.003 - DOI - PubMed

Publication types