bims-unfpre 2024-05-12 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–05–12
twelve papers selected by
Susan Logue, University of Manitoba

The IRE1α/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease.
Mammalian IRE1α dynamically and functionally coalesces with stress granules.
Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
DNMT1 regulates human erythropoiesis by modulating cell cycle and endoplasmic reticulum stress in a stage-specific manner.
The role of the ER stress sensor IRE1 in cardiovascular diseases.
Hhatl ameliorates endoplasmic reticulum stress through autophagy by associating with LC3.
Targeting Integrin α3 Blocks β1 Maturation, Triggers Endoplasmic Reticulum Stress, and Sensitizes Glioblastoma Cells to TRAIL-Mediated Apoptosis.
Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression.
Palmitic acid induces lipid droplet accumulation and senescence in nucleus pulposus cells via ER-stress pathway.
Depleting Cellular Retinoic Acid Binding Protein 1 Impairs UPRmt.
Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.
TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2.

J Clin Invest. 2024 May 09. pii: e174198. [Epub ahead of print]

The IRE1α/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease.

Siyan Cao, Jose Luis Fachi, Kaiming Ma, Alina Ulezko Antonova, Qianli Wang, Zhangying Cai, Randal J Kaufman, Matthew A Ciorba, Parakkal Deepak, Marco Colonna.

  Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. Endoplasmic reticulum (ER) stress is linked to inflammatory bowel disease (IBD). Herein, we used cell culture, mouse models, and human specimens to examine if ER stress in ILC3s impacts IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24h-rhythmic expression pattern of the master ER stress response regulator, IRE1α/XBP1. Proinflammatory cytokine IL-23 selectively stimulated IRE1α/XBP1 in mouse ILC3s through mitochondrial reactive oxygen species (mtROS). IRE1α/XBP1 was activated in ILC3s of mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in Crohn's disease patients before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with response to treatment. We demonstrate that a non-canonical mtROS-IRE1α/XBP1 pathway augments cytokine production by ILC3s and identify XBP1s+ ILC3s as a potential biomarker for predicting response to anti-IL-23 therapies in IBD.

Keywords:  Cell stress; Gastroenterology; Immunology; Inflammatory bowel disease; Innate immunity

DOI:  https://doi.org/10.1172/JCI174198
Nat Cell Biol. 2024 May 07.

Mammalian IRE1α dynamically and functionally coalesces with stress granules.

Songzi Liu, Xiaoge Zhang, Xin Yao, Guan Wang, Shijia Huang, Peng Chen, Mingliang Tang, Jie Cai, Zhuyin Wu, Yiliang Zhang, Rongzhi Xu, Kai Liu, Kangmin He, Yan Wang, Lei Jiang, Qiong A Wang, Liangyou Rui, Jianmiao Liu, Yong Liu.

Upon endoplasmic reticulum (ER) stress, activation of the ER-resident transmembrane protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) initiates a key branch of the unfolded protein response (UPR) through unconventional splicing generation of the transcription factor X-box-binding protein 1 (XBP1s). Activated IRE1 can form large clusters/foci, whose exact dynamic architectures and functional properties remain largely elusive. Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to different stressors, IRE1α clusters are dynamically tethered to SGs at the ER. The cytosolic linker portion of IRE1α possesses intrinsically disordered regions and is essential for its condensation with SGs. Furthermore, disruption of SG assembly abolishes IRE1α clustering and compromises XBP1 mRNA splicing, and such IRE1α-SG coalescence engenders enrichment of the biochemical components of the pro-survival IRE1α-XBP1 pathway during ER stress. Our findings unravel a phase transition mechanism for the spatiotemporal assembly of IRE1α-SG condensates to establish a more efficient IRE1α machinery, thus enabling higher stress-handling capacity.

DOI: https://doi.org/10.1038/s41556-024-01418-7
Nat Commun. 2024 May 10. 15(1): 3982

Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.

Güneş Parlakgül, Song Pang, Leonardo L Artico, Nina Min, Erika Cagampan, Reyna Villa, Renata L S Goncalves, Grace Yankun Lee, C Shan Xu, Gökhan S Hotamışlıgil, Ana Paula Arruda.

The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.

DOI: https://doi.org/10.1038/s41467-024-48272-7
Cell Death Differ. 2024 May 08.

DNMT1 regulates human erythropoiesis by modulating cell cycle and endoplasmic reticulum stress in a stage-specific manner.

Qianqian Yang, Lixiang Chen, Hengchao Zhang, Mengjia Li, Lei Sun, Xiuyun Wu, Huizhi Zhao, Xiaoli Qu, Xiuli An, Ting Wang.

The dynamic balance of DNA methylation and demethylation is required for erythropoiesis. Our previous transcriptomic analyses revealed that DNA methyltransferase 1 (DNMT1) is abundantly expressed in erythroid cells at all developmental stages. However, the role and molecular mechanisms of DNMT1 in human erythropoiesis remain unknown. Here we found that DNMT1 deficiency led to cell cycle arrest of erythroid progenitors which was partially rescued by treatment with a p21 inhibitor UC2288. Mechanically, this is due to decreased DNA methylation of p21 promoter, leading to upregulation of p21 expression. In contrast, DNMT1 deficiency led to increased apoptosis during terminal stage by inducing endoplasmic reticulum (ER) stress in a p21 independent manner. ER stress was attributed to the upregulation of RPL15 expression due to the decreased DNA methylation at RPL15 promoter. The upregulated RPL15 expression subsequently caused a significant upregulation of core ribosomal proteins (RPs) and thus ultimately activated all branches of unfolded protein response (UPR) leading to the excessive ER stress, suggesting a role of DNMT1 in maintaining protein homeostasis during terminal erythroid differentiation. Furthermore, the increased apoptosis was significantly rescued by the treatment of ER stress inhibitor TUDCA. Our findings demonstrate the stage-specific role of DNMT1 in regulating human erythropoiesis and provide new insights into regulation of human erythropoiesis.

DOI: https://doi.org/10.1038/s41418-024-01305-6
Mol Cell Biochem. 2024 May 08.

The role of the ER stress sensor IRE1 in cardiovascular diseases.

Lu Zhou, Xizi Zhu, Shaoqing Lei, Yafeng Wang, Zhongyuan Xia.

  Despite enormous advances in the treatment of cardiovascular diseases, including I/R injury and heart failure, heart diseases remain a leading cause of mortality worldwide. Inositol-requiring enzyme 1 (IRE1) is an evolutionarily conserved sensor endoplasmic reticulum (ER) transmembrane protein that senses ER stress. It manages ER stress induced by the accumulation of unfolded/misfolded proteins via the unfolded protein response (UPR). However, if the stress still persists, the UPR pathways are activated and induce cell death. Emerging evidence shows that, beyond the UPR, IRE1 participates in the progression of cardiovascular diseases by regulating inflammation levels, immunity, and lipid metabolism. Here, we summarize the recent findings and discuss the potential therapeutic effects of IRE1 in the treatment of cardiovascular diseases.

Keywords:  Cardiovascular diseases; Endoplasmic reticulum stress; Inositol-requiring enzyme 1; Unfolded protein response; XBP1

DOI:  https://doi.org/10.1007/s11010-024-05014-z
J Biol Chem. 2024 May 03. pii: S0021-9258(24)01836-2. [Epub ahead of print] 107335

Hhatl ameliorates endoplasmic reticulum stress through autophagy by associating with LC3.

Xingjuan Shi, Jiayu Yao, Yexi Huang, Yushan Wang, Xuan Jiang, Ziwen Wang, Mingming Zhang, Yu Zhang, Xiangdong Liu.

  Endoplasmic reticulum (ER) stress, a common cellular stress response induced by various factors that interfere with cellular homeostasis, may trigger cell apoptosis. Autophagy is an important and conserved mechanism for eliminating aggregated proteins and maintaining protein stability of cells, which is closely associated with ER stress and ER stress-induced apoptosis. In this paper, we report for the first time that Hhatl, an ER-resident protein, is downregulated in response to ER stress. Hhatl overexpression alleviated ER stress and ER stress induced apoptosis in cells treated with tunicamycin or thapsigargin, whereas Hhatl knockdown exacerbated ER stress and apoptosis. Further study showed that Hhatl attenuates ER stress by promoting autophagic flux. Mechanistically, we found that Hhatl promotes autophagy by associating with autophagic protein LC3 (microtubule-associated protein 1A/1B-light chain 3) via the conserved LC3-interacting region (LIR) motif. Noticeably, the LIR motif was essential for Hhatl-regulated promotion of autophagy and reduction of ER stress. These findings demonstrate that Hhatl ameliorates ER stress via autophagy activation by interacting with LC3, thereby alleviating cellular pressure. The study indicates that pharmacological or genetic regulation of Hhatl-autophagy signaling might be potential for mediating ER stress and related diseases.

Keywords:  ER stress; Hhatl; LC3; autophagy

DOI:  https://doi.org/10.1016/j.jbc.2024.107335
Cells. 2024 Apr 26. pii: 753. [Epub ahead of print]13(9):

Targeting Integrin α3 Blocks β1 Maturation, Triggers Endoplasmic Reticulum Stress, and Sensitizes Glioblastoma Cells to TRAIL-Mediated Apoptosis.

Yuki Kuranaga, Bing Yu, Satoru Osuka, Hanwen Zhang, Narra S Devi, Sejong Bae, Erwin G Van Meir.

  Glioblastoma (GBM) is a devastating brain cancer for which new effective therapies are urgently needed. GBM, after an initial response to current treatment regimens, develops therapeutic resistance, leading to rapid patient demise. Cancer cells exhibit an inherent elevation of endoplasmic reticulum (ER) stress due to uncontrolled growth and an unfavorable microenvironment, including hypoxia and nutrient deprivation. Cancer cells utilize the unfolded protein response (UPR) to maintain ER homeostasis, and failure of this response promotes cell death. In this study, as integrins are upregulated in cancer, we have evaluated the therapeutic potential of individually targeting all αβ1 integrin subunits using RNA interference. We found that GBM cells are uniquely susceptible to silencing of integrin α3. Knockdown of α3-induced proapoptotic markers such as PARP cleavage and caspase 3 and 8 activation. Remarkably, we discovered a non-canonical function for α3 in mediating the maturation of integrin β1. In its absence, generation of full length β1 was reduced, immature β1 accumulated, and the cells underwent elevated ER stress with upregulation of death receptor 5 (DR5) expression. Targeting α3 sensitized TRAIL-resistant GBM cancer cells to TRAIL-mediated apoptosis and led to growth inhibition. Our findings offer key new insights into integrin α3's role in GBM survival via the regulation of ER homeostasis and its value as a therapeutic target.

Keywords:  ER stress; brain tumor; death receptor 5; glioblastoma; integrin

DOI:  https://doi.org/10.3390/cells13090753
Cell Metab. 2024 May 03. pii: S1550-4131(24)00134-7. [Epub ahead of print]

Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression.

Qingwen Qian, Mark Li, Zeyuan Zhang, Shannon W Davis, Kamal Rahmouni, Andrew W Norris, Huojun Cao, Wen-Xing Ding, Gökhan S Hotamisligil, Ling Yang.

  Obesity alters levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, dysregulation of which leads to nonalcoholic fatty liver disease (NAFLD). However, the impact of obesity on intra-pituitary homeostasis is largely unknown. Here, we uncovered a blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice and humans. Furthermore, we found that obesity inflames the pituitary gland, leading to impaired pituitary inositol-requiring enzyme 1α (IRE1α)-X-box-binding protein 1 (XBP1) UPR branch, which is essential for protecting against pituitary endocrine defects and NAFLD progression. Intriguingly, pituitary IRE1-deletion resulted in hypothyroidism and suppressed the thyroid hormone receptor B (THRB)-mediated activation of Xbp1 in the liver. Conversely, activation of the hepatic THRB-XBP1 axis improved NAFLD in mice with pituitary UPR defect. Our study provides the first evidence and mechanism of obesity-induced intra-pituitary cellular defects and the pathophysiological role of pituitary-liver UPR communication in NAFLD progression.

Keywords:  IRE1; NAFLD; UPR; obesity; pituitary gland; thyroid hormone

DOI:  https://doi.org/10.1016/j.cmet.2024.04.014
Commun Biol. 2024 May 07. 7(1): 539

Palmitic acid induces lipid droplet accumulation and senescence in nucleus pulposus cells via ER-stress pathway.

Xi Chen, Kun Chen, Jun Hu, Yijun Dong, Menglong Zheng, Jiang Jiang, Qingsong Hu, Wenzhi Zhang.

Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder affecting millions of adults worldwide, but a poor understanding of its pathogenesis has limited the effectiveness of therapy. In the current study, we integrated untargeted LC/MS metabolomics and magnetic resonance spectroscopy data to investigate metabolic profile alterations during IDD. Combined with validation via a large-cohort analysis, we found excessive lipid droplet accumulation in the nucleus pulposus cells of advanced-stage IDD samples. We also found abnormal palmitic acid (PA) accumulation in IDD nucleus pulposus cells, and PA exposure resulted in lipid droplet accumulation and cell senescence in an endoplasmic reticulum stress-dependent manner. Complementary transcriptome and proteome profiles enabled us to identify solute carrier transporter (SLC) 43A3 involvement in the regulation of the intracellular PA level. SLC43A3 was expressed at low levels and negatively correlated with intracellular lipid content in IDD nucleus pulposus cells. Overexpression of SLC43A3 significantly alleviated PA-induced endoplasmic reticulum stress, lipid droplet accumulation and cell senescence by inhibiting PA uptake. This work provides novel integration analysis-based insight into the metabolic profile alterations in IDD and further reveals new therapeutic targets for IDD treatment.

DOI: https://doi.org/10.1038/s42003-024-06248-9
J Cell Signal. 2023 ;4(4): 151-162

Depleting Cellular Retinoic Acid Binding Protein 1 Impairs UPRmt.

Chin-Wen Wei, Thomas Lerdall, Fatimah Najjar, Li-Na Wei.

  Mitochondrial dysfunction underlines neurodegenerative diseases which are mostly characterized by progressive degeneration of neurons. We previously reported that Cellular retinoic acid Binding protein 1 (Crabp1) knockout (CKO) mice spontaneously developed age-dependent motor degeneration, with defects accumulated in spinal motor neurons (MNs), the only cell type in spinal cord that expresses CRABP1. Here we uncovered that mitochondrial DNA (mtDNA) content and the expression of genes involved in respiration were significantly reduced in CKO mouse spinal cord, accompanied by significantly elevated reactive oxygen species (ROS) and unfolded protein load, indicating that CRABP1 deficiency caused mitochondrial dysfunction. Further analyses of spinal cord tissues revealed significant reduction in the expression and activity of superoxide dismutase 2 (SOD2), as well as defected mitochondrial unfolded protein response (UPRmt) pathway, specifically an increase in ATF5 mRNA but not its protein level, which suggested failure in the translational response of ATF5 in CKO. Consistently, eukaryotic initiation factor-2α, (eIF2α) phosphorylation was reduced in CKO spinal cord. In a CRABP1 knockdown MN1 model, siCrabp1-MN1, we validated the cell-autonomous function of CRABP1 in modulating the execution of UPRmt. This study reveals a new functional role for CRABP1 in the execution of mitochondrial stress response, that CRABP1 modulates eIF2α phosphorylation thereby contributing to ATF5 translational response that is needed to mitigate mitochondria stress.

Keywords:  Crabp1; Reactive oxygen species; Unfolded protein response; eIF2α

DOI:  https://doi.org/10.33696/signaling.4.102
Immunity. 2024 Apr 30. pii: S1074-7613(24)00211-5. [Epub ahead of print]

Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Alessandra De Leo, Alessio Ugolini, Xiaoqing Yu, Fabio Scirocchi, Delia Scocozza, Barbara Peixoto, Angelica Pace, Luca D'Angelo, James K C Liu, Arnold B Etame, Aurelia Rughetti, Marianna Nuti, Antonio Santoro, Michael A Vogelbaum, Jose R Conejo-Garcia, Paulo C Rodriguez, Filippo Veglia.

  Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

Keywords:  ER stress; PERK; brain cancer; glioblastoma; glycolysis; histone lactylation; immunosuppression; metabolism; myeloid cells; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.immuni.2024.04.006
Cells. 2024 Apr 25. pii: 747. [Epub ahead of print]13(9):

TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2.

Nabil Ahmed, Christian Preisinger, Thomas Wilhelm, Michael Huber.

  The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information via transcription factors to either regain proteostasis or, depending on the severity, to induce apoptosis. The main transmembrane sensor is IRE1α, which contains cytoplasmic kinase and RNase domains relevant for its activation and the mRNA splicing of the transcription factor XBP1. Mast cell leukemia (MCL) is a severe form of systemic mastocytosis. The inhibition of IRE1α in the MCL cell line HMC-1.2 has anti-proliferative and pro-apoptotic effects, motivating us to elucidate the IRE1α interactors/regulators in HMC-1.2 cells. Therefore, the TurboID proximity labeling technique combined with MS analysis was applied. Gene Ontology and pathway enrichment analyses revealed that the majority of the enriched proteins are involved in vesicle-mediated transport, protein stabilization, and ubiquitin-dependent ER-associated protein degradation pathways. In particular, the AAA ATPase VCP and the oncoprotein MTDH as IRE1α-interacting proteins caught our interest for further analyses. The pharmacological inhibition of VCP activity resulted in the increased stability of IRE1α and MTDH as well as the activation of IRE1α. The interaction of VCP with both IRE1α and MTDH was dependent on ubiquitination. Moreover, MTDH stability was reduced in IRE1α-knockout cells. Hence, pharmacological manipulation of IRE1α-MTDH-VCP complex(es) might enable the treatment of MCL.

Keywords:  ERAD pathway; mastocytosis; metadherin; ubiquitination; valosin-containing protein

DOI:  https://doi.org/10.3390/cells13090747