bims-unfpre 2023-06-25 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–06–25
ten papers selected by
Susan Logue, University of Manitoba

Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity.
HIF1α-dependent hypoxia response in myeloid cells requires IRE1α.
NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation.
Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.
Cross-talk between bioactive lipid mediators and the unfolded protein response in ischemic stroke.
Perturbation of endoplasmic reticulum proteostasis triggers tissue injury in the thyroid gland.
Endoplasmic reticulum stress-responsive microRNAs are involved in the regulation of abiotic stresses in wheat.
Unfolded protein response signature unveils novel insights into breast cancer prognosis and tumor microenvironment.
The development of endoplasmic reticulum-related gene signatures and the immune infiltration analysis of sepsis.
Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response.

Front Immunol. 2023 ;14 1209588

Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity.

Felipe Flores-Santibañez, Sofie Rennen, Dominique Fernández, Clint De Nolf, Evelien Van De Velde, Sandra Gaete González, Camila Fuentes, Carolina Moreno, Diego Figueroa, Álvaro Lladser, Takao Iwawaki, María Rosa Bono, Sophie Janssens, Fabiola Osorio.

  In cancer, activation of the IRE1/XBP1s axis of the unfolded protein response (UPR) promotes immunosuppression and tumor growth, by acting in cancer cells and tumor infiltrating immune cells. However, the role of IRE1/XBP1s in dendritic cells (DCs) in tumors, particularly in conventional type 1 DCs (cDC1s) which are cellular targets in immunotherapy, has not been fully elucidated. Here, we studied the role of IRE1/XBP1s in subcutaneous B16/B78 melanoma and MC38 tumors by generating loss-of-function models of IRE1 and/or XBP1s in DCs or in cDC1s. Data show that concomitant deletion of the RNase domain of IRE1 and XBP1s in DCs and cDC1s does not influence the kinetics of B16/B78 and MC38 tumor growth or the effector profile of tumor infiltrating T cells. A modest effect is observed in mice bearing single deletion of XBP1s in DCs, which showed slight acceleration of melanoma tumor growth and dysfunctional T cell responses, however, this effect was not recapitulated in animals lacking XBP1 only in cDC1s. Thus, evidence presented here argues against a general pro-tumorigenic role of the IRE1/XBP1s pathway in tumor associated DC subsets.

Keywords:  IRE1; XBP1; antitumor immune response; cDC1; dendritic cells; immunity; melanoma; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2023.1209588
J Neuroinflammation. 2023 Jun 21. 20(1): 145

HIF1α-dependent hypoxia response in myeloid cells requires IRE1α.

Gaëlle Mawambo, Malika Oubaha, Yusuke Ichiyama, Guillaume Blot, Sergio Crespo-Garcia, Agnieszka Dejda, François Binet, Roberto Diaz-Marin, Christina Sawchyn, Mikhail Sergeev, Rachel Juneau, Randal J Kaufman, El Bachir Affar, Frédérick A Mallette, Ariel M Wilson, Przemyslaw Sapieha.

  Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to function under low oxygen tension and metabolic stress. While Hypoxia-Inducible Factor (HIF)-1α has been shown to be essential for the inflammatory response of myeloid cells by regulating the metabolic switch to glycolysis, less is known about how HIF1α is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1α (IRE1α/XBP1) axis in order to initiate HIF1α-dependent production of cytokines such as IL1β, IL6 and VEGF-A. Knockout of either HIF1α or IRE1α in myeloid cells ameliorates vascular phenotypes in a model of retinal pathological angiogenesis driven by sterile inflammation. Thus, pathways associated with ER stress, in partnership with HIF1α, may co-regulate immune adaptation to low oxygen.

Keywords:  Angiogenesis; ER stress; HIF1α; Hypoxia; IRE1α; Inflammation; Microglia; Mononuclear phagocytes; Myeloid; Retina

DOI:  https://doi.org/10.1186/s12974-023-02793-y
Nat Commun. 2023 Jun 23. 14(1): 3761

NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation.

Isidoro Cobo, Sumit Paliwal, Cristina Bodas, Irene Felipe, Júlia Melià-Alomà, Ariadna Torres, Jaime Martínez-Villarreal, Marina Malumbres, Fernando García, Irene Millán, Natalia Del Pozo, Joo-Cheol Park, Ray J MacDonald, Javier Muñoz, Raúl Méndez, Francisco X Real.

Pancreatic acinar cells rely on PTF1 and other transcription factors to deploy their transcriptional program. We identify NFIC as a NR5A2 interactor and regulator of acinar differentiation. NFIC binding sites are enriched in NR5A2 ChIP-Sequencing peaks. Nfic knockout mice have a smaller, histologically normal, pancreas with reduced acinar gene expression. NFIC binds and regulates the promoters of acinar genes and those involved in RNA/protein metabolism, and Nfic knockout pancreata show defective ribosomal RNA maturation. NFIC dampens the endoplasmic reticulum stress program through binding to gene promoters and is required for resolution of Tunicamycin-mediated stress. NFIC is down-regulated during caerulein pancreatitis and is required for recovery after damage. Normal human pancreata with low levels of NFIC transcripts display reduced expression of genes down-regulated in Nfic knockout mice. NFIC expression is down-regulated in mouse and human pancreatic ductal adenocarcinoma. Consistently, Nfic knockout mice develop a higher number of mutant Kras-driven pre-neoplastic lesions.

DOI: https://doi.org/10.1038/s41467-023-39291-x
Science. 2023 Jun 23. 380(6651): eadh9351

Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.

Déborah Naón, María Isabel Hernández-Alvarez, Satoko Shinjo, Milosz Wieczor, Saska Ivanova, Olga Martins de Brito, Albert Quintana, Juan Hidalgo, Manuel Palacín, Pilar Aparicio, Juan Castellanos, Luis Lores, David Sebastián, Sonia Fernández-Veledo, Joan Vendrell, Jorge Joven, Modesto Orozco, Antonio Zorzano, Luca Scorrano.

In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities.

DOI: https://doi.org/10.1126/science.adh9351
Prostaglandins Other Lipid Mediat. 2023 Jun 16. pii: S1098-8823(23)00057-6. [Epub ahead of print] 106760

Cross-talk between bioactive lipid mediators and the unfolded protein response in ischemic stroke.

Tarvi Teder, Jesper Z Haeggström, Mikko Airavaara, Helike Lõhelaid.

  Ischemic cerebral stroke is a severe medical condition that affects about 15 million people every year and is the second leading cause of death and disability globally. Ischemic stroke results in neuronal cell death and neurological impairment. Current therapies may not adequately address the deleterious metabolic changes and may increase neurological damage. Oxygen and nutrient depletion along with the tissue damage result in endoplasmic reticulum (ER) stress, including the Unfolded Protein Response (UPR), and neuroinflammation in the affected area and cause cell death in the lesion core. The spatio-temporal production of lipid mediators, either pro-inflammatory or pro-resolving, decides the course and outcome of stroke. The modulation of the UPR as well as the resolution of inflammation promotes post-stroke cellular viability and neuroprotection. However, studies about the interplay between the UPR and bioactive lipid mediators remain elusive and this review gives insights about the crosstalk between lipid mediators and the UPR in ischemic stroke. Overall, the treatment of ischemic stroke is often inadequate due to lack of effective drugs, thus, this review will provide novel therapeutical strategies that could promote the functional recovery from ischemic stroke.

Keywords:  ER stress; Unfolded Protein Response; bioactive lipid mediators; cerebral ischemic stroke

DOI:  https://doi.org/10.1016/j.prostaglandins.2023.106760
JCI Insight. 2023 06 22. pii: e169937. [Epub ahead of print]8(12):

Perturbation of endoplasmic reticulum proteostasis triggers tissue injury in the thyroid gland.

Xiaohan Zhang, Crystal Young, Xiao-Hui Liao, Samuel Refetoff, Mauricio Torres, Yaron Tomer, Mihaela Stefan-Lifshitz, Hao Zhang, Dennis Larkin, Deyu Fang, Ling Qi, Peter Arvan.

  Defects in endoplasmic reticulum (ER) proteostasis have been linked to diseases in multiple organ systems. Here we examined the impact of perturbation of ER proteostasis in mice bearing thyrocyte-specific knockout of either HRD1 (to disable ER-associated protein degradation [ERAD]) or ATG7 (to disable autophagy) in the absence or presence of heterozygous expression of misfolded mutant thyroglobulin (the most highly expressed thyroid gene product, synthesized in the ER). Misfolding-inducing thyroglobulin mutations are common in humans but are said to yield only autosomal-recessive disease - perhaps because misfolded thyroglobulin protein might undergo disposal by ERAD or ER macroautophagy. We find that as single defects, neither ERAD, nor autophagy, nor heterozygous thyroglobulin misfolding altered circulating thyroxine levels, and neither defective ERAD nor defective autophagy caused any gross morphological change in an otherwise WT thyroid gland. However, heterozygous expression of misfolded thyroglobulin itself triggered significant ER stress and individual thyrocyte death while maintaining integrity of the surrounding thyroid epithelium. In this context, deficiency of ERAD (but not autophagy) resulted in patchy whole-follicle death with follicular collapse and degeneration, accompanied by infiltration of bone marrow-derived macrophages. Perturbation of thyrocyte ER proteostasis is thus a risk factor for both cell death and follicular demise.

Keywords:  Cell Biology; Protein misfolding

DOI:  https://doi.org/10.1172/jci.insight.169937
Plant Cell Rep. 2023 Jun 21.

Endoplasmic reticulum stress-responsive microRNAs are involved in the regulation of abiotic stresses in wheat.

Yong Chen, Xing Yu.

   KEY MESSAGE: ER stress-responsive miRNAs, tae-miR164, tae-miR2916, and tae-miR396e-5p, are essential in response to abiotic stress. Investigating ER stress-responsive miRNAs is necessary to improve plant tolerance to environmental stress. MicroRNAs (miRNAs) play vital regulatory roles in plant responses to environmental stress. Recently, the endoplasmic reticulum (ER) stress pathway, an essential signalling pathway in plants in response to adverse conditions, has been widely studied in model plants. However, miRNAs associated with ER stress response remain largely unknown. Using high-throughput sequencing, three ER stress-responsive miRNAs, tae-miR164, tae-miR2916, and tae-miR396e-5p were identified, and their target genes were confirmed. These three miRNAs and their target genes actively responded to dithiothreitol, polyethylene glycol, salt, heat, and cold stresses. Furthermore, in some instances, the expression patterns of the miRNAs and their corresponding target genes were contrasting. Knockdown of tae-miR164, tae-miR2916, or tae-miR396e-5p using a barley stripe mosaic virus-based miRNA silencing system substantially enhanced the tolerance of wheat plants to drought, salt, and heat stress. Under conditions involving these stresses, inhibiting the miR164 function by using the short tandem target mimic approach in Arabidopsis thaliana resulted in phenotypes consistent with those of miR164-silenced wheat plants. Correspondingly, overexpression of tae-miR164 in Arabidopsis resulted in a decreased tolerance to drought stress and, to some extent, a decrease in tolerance to salt and high temperature. These results revealed that tae-miR164 plays a negative regulatory role in wheat/Arabidopsis in response to drought, salt, and heat stress. Taken together, our study provides new insights into the regulatory role of ER stress-responsive miRNAs in abiotic stress responses.

Keywords:  Arabidopsis thaliana (L.) Heynh.; Drought stress; Heat stress; Salt stress; Triticum aestivum L.; microRNA

DOI:  https://doi.org/10.1007/s00299-023-03040-7
Cancer Genet. 2023 Jun 14. pii: S2210-7762(23)00034-0. [Epub ahead of print]276-277 17-29

Unfolded protein response signature unveils novel insights into breast cancer prognosis and tumor microenvironment.

Nanyang Zhou, Dejia Kong, Qiao Lin, Xiaojing Yang, Dan Zhou, Lihua Lou, Feixiang Huang.

   BACKGROUND: The critical role of the unfolded protein response (UPR) in tumorigenesis is widely acknowledged, yet the precise molecular mechanisms underlying its contribution to breast cancer (BC) have not been fully elucidated. The present study aimed to comprehensively explore the expression characteristics and prognostic significance of UPR-related genes in breast cancer METHODS: The transcriptome and clinical data of breast cancer were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, respectively. Differential expression analysis was conducted on UPR-related genes, and the resulting genes were employed for consensus clustering analysis. A breast cancer prognosis risk model was constructed using univariate, least absolute shrinkage and selection operator (LASSO), and multivariable Cox regression analyses. Difference in survival outcomes between groups were analyzed Kaplan-Meier survival analysis, and receiver operating characteristic (ROC) curve was used to assess predictive performance. The relationship between the risk model and clinical-pathological characteristics, immune infiltration, immunotherapy response, and drug sensitivity was assessed.
RESULTS: Differential expression analysis identified 10 UPR-related genes that were differentially expressed in breast cancer. Using the expression matrix of these genes, two molecular subtypes of breast cancer were characterized, which displayed significant differences in prognostic and immune infiltration characteristics. Drawing from the gene expression profiles that distinguish between the molecular subtypes, a prognostic risk scoring model comprising eight genes was developed. This model stratified BC patients from both the training and validation cohorts into high-risk and low-risk groups. Patients in the low-risk group had better prognoses, while those with advanced clinical stage and T stage exhibited higher risk scores. The high- and low-risk groups exhibited notable disparities in immune cell infiltration and the expression of multiple immune checkpoint-related genes. Additionally, the low-risk group demonstrated elevated immunophenoscore, Merck18, CD274, and CAF scores compared to the high-risk group, along with a lesser sensitivity to chemotherapy drugs. These results suggest that patients within the low-risk group may potentially benefit more from immunotherapy and chemotherapy interventions.
CONCLUSIONS: This study developed a novel UPR-derived risk signature, which could robustly predict the survival outcome, immune microenvironment, and chemotherapy response of patients with breast cancer.

Keywords:  Breast cancer; Chemotherapy; Immune infiltration; Nomogram; Unfolded protein response

DOI:  https://doi.org/10.1016/j.cancergen.2023.06.001
Front Immunol. 2023 ;14 1183769

The development of endoplasmic reticulum-related gene signatures and the immune infiltration analysis of sepsis.

Yi Zhou, Yifang Chen, Jianbo Li, Zailin Fu, Qian Chen, Wei Zhang, Huan Luo, Minghua Xie.

   Background: Sepsis is a complex condition involving multiorgan failure, resulting from the hosts' deleterious systemic immune response to infection. It is characterized by high mortality, with limited effective detection and treatment options. Dysregulated endoplasmic reticulum (ER) stress is directly involved in the pathophysiology of immune-mediated diseases.
Methods: Clinical samples were obtained from Gene Expression Omnibus datasets (i.e., GSE65682, GSE54514, and GSE95233) to perform the differential analysis in this study. A weighted gene co-expression network analysis algorithm combining multiple machine learning algorithms was used to identify the diagnostic biomarkers for sepsis. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and the single-sample gene set enrichment analysis algorithm were used to analyze immune infiltration characteristics in sepsis. PCR analysis and western blotting were used to demonstrate the potential role of TXN in sepsis.
Results: Four ERRGs, namely SET, LPIN1, TXN, and CD74, have been identified as characteristic diagnostic biomarkers for sepsis. Immune infiltration has been repeatedly proved to play a vital role both in sepsis and ER. Subsequently, the immune infiltration characteristics result indicated that the development of sepsis is mediated by immune-related function, as four diagnostic biomarkers were strongly associated with the immune infiltration landscape of sepsis. The biological experiments in vitro and vivo demonstrate TXN is emerging as crucial player in maintaining ER homeostasis in sepsis.
Conclusion: Our research identified novel potential biomarkers for sepsis diagnosis, which point toward a potential strategy for the diagnosis and treatment of sepsis.

Keywords:  diagnostic biomarkers; endoplasmic reticulum; immune infiltration; machine learning; sepsis

DOI:  https://doi.org/10.3389/fimmu.2023.1183769
Nat Commun. 2023 Jun 22. 14(1): 3716

Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response.

Eunah Kim, Andrea Annibal, Yujin Lee, Hae-Eun H Park, Seokjin Ham, Dae-Eun Jeong, Younghun Kim, Sangsoon Park, Sujeong Kwon, Yoonji Jung, JiSoo Park, Sieun S Kim, Adam Antebi, Seung-Jae V Lee.

Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown, in particular at the organism level. Here we show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyzes the conversion of citrate to isocitrate, inhibits immunity against pathogenic bacteria in C. elegans. We find that the genetic inhibition of aco-2 decreases the level of oxaloacetate. This increases the mitochondrial unfolded protein response, subsequently upregulating the transcription factor ATFS-1, which contributes to enhanced immunity against pathogenic bacteria. We show that the genetic inhibition of mammalian ACO2 increases immunity against pathogenic bacteria by modulating the mitochondrial unfolded protein response and oxaloacetate levels in cultured cells. Because mitochondrial aconitase is highly conserved across phyla, a therapeutic strategy targeting ACO2 may eventually help properly control immunity in humans.

DOI: https://doi.org/10.1038/s41467-023-39393-6