Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance

Rubio-Patiño, Camila; Bossowski, Jozef P.; Donatis, Gian Marco De; Mondragón, Laura; Villa, Elodie; Aira, Lazaro E.; Chiche, Johanna; Mhaidly, Rana; Lebeaupin, Cynthia; Marchetti, Sandrine; Voutetakis, Konstantinos; Chatziioannou, Aristotelis; Castelli, Florence; Lamourette, Patricia; Chu‐Van, Emeline; Fenaille, François; Avril, Tony; Passeron, Thierry; Patterson, John B.; Verhoeyen, Els; Bailly-Maître, Béatrice; Chevet, Éric; Ricci, Jean-Ehrland

doi:10.1016/j.cmet.2018.02.009

Cited by 111 publications

(94 citation statements)

References 49 publications

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“…It was recently described that ATF4 mediates increased amino acid uptake upon glutamine deprivation [295]. Furthermore, a low protein diet leads to the upregulation of cytokines mediated by IRE1 and RIG1 which results in an anticancer immune response in tumours [296]. In summary, these findings show the importance of the various UPR arms in cell metabolism and energy homeostasis with effects not only on the cell itself but also on the whole cellular environment.…”

Section: Amino Acid Metabolismmentioning

confidence: 66%

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

et al. 2018

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The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

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Section: Amino Acid Metabolismmentioning

confidence: 66%

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

et al. 2018

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“…Furthermore, angiogenesis, which is essential for tumor dormancy, is supported by the IRE1/XBP1 pathway (54,60,61). Finally, the activation of the IRE1 pathway was also linked to the recruitment of T cells in various tumors (62). Thus, in some types of tumors, inhibition of the IRE1/XBP1 pathway can serve as a multipronged strategy to facilitate tumor immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

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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“…In CT26‐BALB/c and B16‐C57BL/6 tumor‐bearing mice, a low‐protein diet activated the IRE1α arm of the UPR leading to reduced tumor burden. Increased IRE1α activity and subsequent activation of RIDD, as measured by increased expression of RIG1, enhanced recruitment of CD8‐positive cells through induction of IFNγ and CXCL10, thus initiating antitumor surveillance response in these xenograft models . Downregulation of IRE1α was also reported to drive tumorigenesis.…”

Section: Ire1α Expression In Human Cancermentioning

confidence: 91%

“…Increased IRE1α activity and subsequent activation of RIDD, as measured by increased expression of RIG1, enhanced recruitment of CD8-positive cells through induction of IFNγ and CXCL10, thus initiating antitumor surveillance response in these xenograft models. 30 RNase in cancer pathogenesis make this analysis complex. This complexity is further increased by observations that targeted deletion of Xbp1 in mouse models leads to hyperactivation of IRE1α and RIDD 34 suggesting that there may be interactions between these two outputs of the IRE1α RNase that are yet to be understood.…”

Section: Ire1α Expression In Human Cancermentioning

confidence: 99%

The multiple roles of the unfolded protein response regulator IRE1α in cancer

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Mogre

Son

et al. 2019

Molecular Carcinogenesis

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Cancer is associated with a number of conditions such as hypoxia, nutrient deprivation, cellular redox, and pH changes that result in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) and trigger a stress response known as the unfolded protein response (UPR). The UPR is a conserved cellular survival mechanism mediated by the ER transmembrane proteins activating transcription factor 6, protein kinase‐like endoplasmic reticulum kinase, and inositol‐requiring enzyme 1α (IRE1α) that act to resolve ER stress and promote cell survival. IRE1α is a kinase/endoribonuclease (RNase) with multiple activities including unconventional splicing of the messenger RNA (mRNA) for the transcription factor X‐Box Binding Protein 1 (XBP1), degradation of other mRNAs in a process called regulated IRE1α‐dependent decay (RIDD) and activation of a pathway leading to c‐Jun N‐terminal kinase phosphorylation. Each of these outputs plays a role in the adaptive and cell death responses to ER stress. Many studies indicate an important role for XBP1 and RIDD functions in cancer and new studies suggest that these two functions of the IRE1α RNase can have opposing functions in the early and later stages of cancer pathogenesis. Finally, as more is learned about the context‐dependent role of IRE1α in cancer development, specific small molecule inhibitors and activators of IRE1α could play an important role in counteracting the protective shield provided by ER stress signaling in cancer cells.

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Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance

Cited by 111 publications

References 49 publications

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

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

The multiple roles of the unfolded protein response regulator IRE1α in cancer

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