Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation

Hosomi, Shuhei; Grootjans, Joep; Tschurtschenthaler, Markus; Krupka, Niklas; Matute, Juan D.; Flak, Magdalena B.; Martı́nez-Naves, Eduardo; Moral, Manuel Gómez del; Glickman, Jonathan N.; Ohira, Mizuki; Lanier, Lewis L.; Kaser, Arthur; Blumberg, Richard S.

doi:10.1084/jem.20162041

Cited by 48 publications

(43 citation statements)

References 55 publications

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“…This mechanism is different than what was proposed for IRE1-mediated regulation of Ig synthesis (45) or caspase 2 levels (66), in which the IRE1-dependent mRNA decay pathway dominated. Surprisingly, a different mechanism has been described for the regulation of the UL16 binding protein family of NKG2D ligands, which implicated CHOP as a transcription activator downstream of the IRE1/XBP1 pathway in epithelial cells (41). Our data show no effect on MICA expression of the PERK arm of the UPR, which is the main regulator of CHOP in most cell lines, and no effect for the removal of CHOP itself.…”

Section: Discussioncontrasting

confidence: 59%

“…1 and 2) adds an important layer to the implications of blocking IRE1 for improved immunotherapy. Caution is needed, however, because the inactivation of XBP1 in the gut may lead to conditions of enteritis (41,65).…”

Section: Discussionmentioning

confidence: 99%

“…These data indicate that the reduction of MICA surface expression under ER stress depends on IRE1. It should also be noted that a recent study identified CHOP as regulator of ULBP1, -5, and -6, but not MICA/B, in murine and human epithelial cells (41). To demonstrate that this regulation is most likely different, we generated CHOP-deficient MEL624 cells.…”

Section: Induction Of Er Stress By Tm Inhibits Mica Expression In An mentioning

confidence: 99%

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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

et al. 2018

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The unfolded protein response (UPR) is an adaptive signaling pathway activated in response to endoplasmic reticulum (ER) stress. The effectors of the UPR are potent transcription activators; however, some genes are suppressed by ER stress at the mRNA level. The mechanisms underlying UPR‐mediated gene suppression are less known. Exploration of the effect of UPR on NK cells ligand expression found that the transcription of NK group 2 member D (NKG2D) ligand major histocompatibility complex class I polypeptide‐related sequence A/B (MICA/B) is suppressed by the inositol‐requiring enzyme 1 (IRE1)/X‐box binding protein 1 (XBP1) pathway of the UPR. Deletion of IRE1 or XBP1 was sufficient to promote mRNA and surface levels of MICA. Accordingly, NKG2D played a greater role in the killing of IRE1/XBP1 knockout target cells. Analysis of effectors downstream to XBP1s identified E2F transcription factor 1 (E2F1) as linking UPR and MICA transcription. The inverse correlation between XBP1 and E2F1 or MICA expression was corroborated in RNA‐Seq analysis of 470 primary melanoma tumors. While mechanisms that connect XBP1 to E2F1 are not fully understood, we implicate a few microRNA molecules that are modulated by ER stress and possess dual suppression of E2F1 and MICA. Because of the importance of E2F1 and MICA in cancer progression and recognition, these observations could be exploited for cancer therapy by manipulating the UPR in tumor cells.—Obiedat, A., Seidel, E., Mahameed, M., Berhani, O., Tsukerman, P., Voutetakis, K., Chatziioannou, A., McMahon, M., Avril, T., Chevet, E., Mandelboim, O., Tirosh, B. Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1. FASEB J. 33, 3481–3495 (2019). http://www.fasebj.org

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Section: Discussioncontrasting

confidence: 59%

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confidence: 99%

Section: Induction Of Er Stress By Tm Inhibits Mica Expression In An mentioning

confidence: 99%

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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

et al. 2018

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“…A recent report investigated the impact of the ER stress response in regulating NKG2D ligands and observed induction of human ULBP1, as well as mouse MULT1 . Mouse MULT1 is considered a homolog of human ULBP1.…”

Section: The Integrated Stress Response Regulates Human Ulbp1 Expressmentioning

confidence: 99%

Dysregulated cellular functions and cell stress pathways provide critical cues for activating and targeting natural killer cells to transformed and infected cells

Raulet

Marcus

Coscoy

2017

Immunological Reviews

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Summary Natural killer (NK) cells recognize and kill cancer cells and infected cells by engaging cell surface ligands that are induced preferentially or exclusively on these cells. These ligands are recognized by activating receptors on NK cells, such as NKG2D. In addition to activation by cell surface ligands, the acquisition of optimal effector activity by NK cells is driven in vivo by cytokines and other signals. This review addresses a developing theme in NK cell biology: that NK-activating ligands on cells, and the provision of cytokines and other signals that drive high effector function in NK cells, are driven by abnormalities that arise from transformation or the infected state. The pathways include genomic damage, which causes self DNA to be exposed in the cytosol of affected cells, where it activates the DNA sensor cGAS. The resulting signaling induces NKG2D ligands and also mobilizes NK cell activation. Other key pathways that regulate NKG2D ligands include PI-3 kinase activation, histone acetylation, and the integrated stress response. This review summarizes the roles of these pathways and their relevance in both viral infections and cancer.

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“…Although ER stress causes a mild form of enteritis in Xbp1 ΔIEC mice (7), loss of PERK-induced autophagy in Atg16l1;Xbp1 ΔIEC mice results in a transmural, discontinuous ileitis reminiscent of human Crohn’s disease (1). Notably, in Xbp1 ΔIEC mice, CHOP signaling induces the expression of the NKG2D ligand UL16-binding protein 1 (ULBP1), which causes an increase in NKG2D-expressing ILC1s and natural killer immune cells in the intraepithelial compartment (8). This is interesting because Bel et al .…”

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confidence: 99%

The road to Crohn's disease

Kaser

Blumberg

2017

Science

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Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation

Cited by 48 publications

References 55 publications

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

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

Dysregulated cellular functions and cell stress pathways provide critical cues for activating and targeting natural killer cells to transformed and infected cells

The road to Crohn's disease

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