Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1

Obiedat, Akram; Seidel, Einat; Mahameed, Mohamed; Berhani, Orit; Tsukerman, Pinchas; Voutetakis, Konstantinos; Chatziioannou, Aristotelis; McMahon, Mari; Avril, Tony; Chevet, Éric; Mandelboim, Ofer; Tirosh, Boaz

doi:10.1096/fj.201801350rr

Cited by 24 publications

(20 citation statements)

References 71 publications

(67 reference statements)

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“…Epigenetic and transcriptional regulation mechanisms are often perturbed in tumor cells, and NKG2D-L expression may be altered. In melanoma, endoplasmic reticulum stress can reduce MICA transcription by modulating activation of the transcription factor E2F1 (66). Indeed, immature isoforms of MICA are retained in the endoplasmic reticulum, resulting in limited membrane-display of MICA (67).…”

Section: Regulation Of Nkg2d and Nkg2d-l Expressionmentioning

confidence: 99%

NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment

et al. 2019

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The antitumor functions of NK cells are regulated by the integration of positive and negative signals triggered by numerous membrane receptors present on the NK cells themselves. Among the main activating receptors, NKG2D binds several stress-induced molecules on tumor targets. Engagement of NKG2D by its ligands (NKG2D-Ls) induces NK cell activation leading to production of cytokines and target cell lysis. These effects have therapeutic potential as NKG2D-Ls are widely expressed by solid tumors, whereas their expression in healthy cells is limited. Here, we describe the genetic and environmental factors regulating the NKG2D/NKG2D-L pathway in tumors. NKG2D-L expression is linked to cellular stress and cell proliferation, and has been associated with oncogenic mutations. Tumors have been found to alter their to NKG2D-L expression as they progress, which interferes with the antitumor function of the pathway. Nevertheless, this pathway could be advantageously exploited for cancer therapy. Various cancer treatments, including chemotherapy and targeted therapies, indirectly interfere with the cellular and soluble forms of NKG2D-Ls. In addition, NKG2D introduced into chimeric antigen receptors in T- and NK cells is a promising tumor immunotherapy approach.

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Section: Regulation Of Nkg2d and Nkg2d-l Expressionmentioning

confidence: 99%

NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment

et al. 2019

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“…Knockout cells were produced as previously described [24]. In brief, cells were transfected with constructs targeting IRE1, PERK, or CHOP.…”

Section: Generation Of Upr-deficient Cells By Crispr/cas9 Editingmentioning

confidence: 99%

“…The UPR through the IRE1 arm suppresses the transcription of MICA and MICB [24]. To characterize the comprehensive effect of ER stress on the expression of NK cell ligands, we analyzed their expression on melanoma 624 cells after treatment with the ER stress inducer thapsigargin (Tg).…”

Section: Er Stress Upregulates B7h6 In a Perk-dependent Mannermentioning

confidence: 99%

“…This was unexpected, as protein trafficking is usually perturbed by agents that nondiscriminatorily damage protein folding in the ER, such as Tg. We used a panel of IRE1 or PERK-deficient melanoma 624 cells (described in [24]) to examine which pathways of the UPR are involved in the elevation of B7H6 expression. B7H6 surface expression was increased on IRE1 KO cells upon Tg treatment similarly to wt cells.…”

Section: Er Stress Upregulates B7h6 In a Perk-dependent Mannermentioning

confidence: 99%

“…The UPR is involved as well in immune cell recognition. For instance, the UPR plays a role in the regulation of the expression of stress-induced ligands of natural killer cells, MICA, and B (major histocompatibility complex class I polypeptide-related sequence A and B) and ULBPs (UL16 binding proteins) [23,24]. B7H6 is also a stress-induced NK cell ligand, though its regulation by the UPR has not been reported [4].…”

Section: Introductionmentioning

confidence: 99%

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The integrated stress response promotes B7H6 expression

et al. 2019

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The B7 family member, B7H6, is a ligand for the natural killer cell receptor NKp30. B7H6 is hardly expressed on normal tissues, but undergoes upregulation on different types of tumors, implicating it as an attractive target for cancer immunotherapy. The molecular mechanisms that control B7H6 expression are poorly understood. We report that in contrast to other NK cell ligands, endoplasmic reticulum (ER) stress upregulates B7H6 mRNA levels and surface expression. B7H6 induction by ER stress requires protein kinase R-like ER kinase (PERK), one of the three canonical sensors of the unfolded protein response. PERK phosphorylates eIF2α, which regulates protein synthesis and gene expression. Because eIF2α is phosphorylated by several kinases following different stress conditions, the program downstream to eIF2α phosphorylation is called the integrated stress response (ISR). Several drugs were reported to promote the ISR. Nelfinavir and lopinavir, two clinically approved HIV protease inhibitors, promote eIF2α phosphorylation by different mechanisms. We show that nelfinavir and lopinavir sustainably instigate B7H6 expression at their pharmacologically relevant concentrations. As such, ER stress and ISR conditions sensitize melanoma targets to CART cells directed against B7H6. Our study highlights a novel mechanism to induce B7H6 expression and suggests a pharmacological approach to improve B7H6-directed immunotherapy.

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Inositol‐Requiring Enzyme 1α–Mediated Synthesis of Monounsaturated Fatty Acids as a Driver of B Cell Differentiation and Lupus‐like Autoimmune Disease

Zhang

Gui

Wang

et al. 2021

Arthritis & Rheumatology

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Objective. To explore the molecular mechanisms underlying dysregulation of lipid metabolism in the pathogenesis of systemic lupus erythematosus (SLE).Methods. B cells in peripheral blood from patients with SLE and healthy controls were stained with BODIPY dye for detection of lipids. Mice with targeted knockout of genes for B cell-specific inositol-requiring enzyme 1α (IRE-1α) and stearoyl-coenzyme A desaturase 1 (SCD-1) were used for studying the influence of the IRE-1α/SCD-1/SCD-2 pathway on B cell differentiation and autoantibody production. The preclinical efficacy of IRE-1α suppression as a treatment for lupus was tested in MRL.Fas lpr mice.Results. In cultures with mouse IRE-1α-null B cells, supplementation with monounsaturated fatty acids largely rescued differentiation of plasma cells from B cells, indicating that the compromised capacity of B cell differentiation in the absence of IRE-1α may be attributable to a defect in monounsaturated fatty acid synthesis. Moreover, activation with IRE-1α/X-box binding protein 1 (XBP-1) was required to facilitate B cell expression of SCD-1 and SCD-2, which are 2 critical enzymes that catalyze monounsaturated fatty acid synthesis. Mice with targeted Scd1 gene deletion displayed a phenotype that was similar to that of IRE-1α-deficient mice, with diminished B cell differentiation into plasma cells. Importantly, in B cells from patients with lupus, both IRE-1α expression and Xbp1 messenger RNA splicing were significantly increased, and this was positively correlated with the expression of both Scd1 and Scd2 as well as with the amount of B cell lipid deposition. In MRL.Fas lpr mice, both genetic and pharmacologic suppression of IRE-1α protected against the pathologic development and progression of lupus-like autoimmune disease.Conclusion. The results of this study reveal a molecular link in the dysregulation of lipid metabolism in the pathogenesis of lupus, demonstrating that the IRE-1α/XBP-1 pathway controls plasma cell differentiation through SCD-1/SCD-2-mediated monounsaturated fatty acid synthesis. These findings provide a rationale for targeting IRE-1α and monounsaturated fatty acid synthesis in the treatment of patients with SLE.

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Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1

Cited by 24 publications

References 71 publications

NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment

NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment

The integrated stress response promotes B7H6 expression

Inositol‐Requiring Enzyme 1α–Mediated Synthesis of Monounsaturated Fatty Acids as a Driver of B Cell Differentiation and Lupus‐like Autoimmune Disease

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