bims-unfpre 2023-07-16 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–07–16
eight papers selected by
Susan Logue, University of Manitoba

Autophagy-ER stress crosstalk controls mucus secretion and susceptibility to gut inflammation.
Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis.
Stress and Liver Fibrogenesis: Understanding the role and regulation of stress response pathways in Hepatic Stellate Cells.
Role of endoplasmic reticulum stress response in liver regeneration.
Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity.
Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2.
Marchf6 E3 ubiquitin ligase critically regulates endoplasmic reticulum stress, ferroptosis, and metabolic homeostasis in POMC neurons.
Inhibition of protein translation under matrix-deprivation stress in breast cancer cells.

Autophagy. 2023 Jul 12. 1-3

Autophagy-ER stress crosstalk controls mucus secretion and susceptibility to gut inflammation.

Maria Naama, Shai Bel.

  Mucus secretion from colonic goblet cells is an important host defense mechanism against the harsh lumenal environment. Yet how mucus secretion is regulated is not well understood. We discovered that constitutive activation of macroautophagy/autophagy via BECN1 (beclin 1) relieves endoplasmic reticulum (ER) stress in goblet cells, which in turn produce a thicker and less penetrable mucus barrier. Pharmacological reduction of the ER stress or activation of the unfolded protein response (UPR) in mice, regardless of autophagy activation, lead to excess mucus secretion. This regulation of mucus secretion by ER stress is microbiota-dependent and requires the activity of the intracellular sensor NOD2 (nucleotide-binding oligomerization domain containing 2). Excess mucus production in the colon alters the gut microbiota and protects from chemical- and infection-driven inflammation. Our findings provide new insights into the mechanisms by which autophagy regulates mucus secretion and susceptibility to intestinal inflammation.Abbreviations:BECN1- Beclin 1; ER- endoplasmic reticulum; UPR - unfolded protein response; NOD2 - nucleotide-binding oligomerization domain containing 2; IBD- inflammatory bowel disease; BCL2- B cell leukemia/lymphoma 2; TUDCA- tauroursodeoxycholic acid; ATG16L1- autophagy related 16 like 1; LRRK2- leucine-rich repeat kinase 2.

Keywords:  Autophagy; BECN1; Crohn’s disease; ER stress; Goblet; Mucus

DOI:  https://doi.org/10.1080/15548627.2023.2228191
J Clin Invest. 2023 Jul 11. pii: e167359. [Epub ahead of print]

Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis.

Deepika Awasthi, Sahil Chopra, Byuri A Cho, Alexander Emmanuelli, Tito A Sandoval, Sung-Min Hwang, Chang-Suk Chae, Camilla Salvagno, Chen Tan, Liliana Vasquez-Urbina, Jose J Fernandez Rodriguez, Sara F Santagostino, Takao Iwawaki, E Alfonso Romero-Sandoval, Mariano Sanchez Crespo, Diana K Morales, Iliyan D Iliev, Tobias M Hohl, Juan R Cubillos-Ruiz.

  Recognition of pathogen-associated molecular patterns can trigger the IRE1α arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive. Here, we report that systemic infection with the human opportunistic fungal pathogen Candida albicans induces proinflammatory IRE1α hyperactivation in myeloid cells that leads to fatal kidney immunopathology. Mechanistically, simultaneous activation of the TLR/IL-1R adaptor protein MyD88 and the C-type lectin receptor Dectin-1 by C. albicans induced NADPH oxidase-driven generation of reactive oxygen species that caused ER stress and IRE1α-dependent overexpression of key inflammatory mediators such as IL-1β, IL-6, CCL5, PGE2 and TNFα. Selective ablation of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, mitigated kidney inflammation and prolonged the survival of mice with systemic C. albicans infection. Therefore, controlling IRE1α hyperactivation may be useful for impeding the immunopathogenic progression of disseminated candidiasis.

Keywords:  Cell stress; Fungal infections; Immunology; Infectious disease; Innate immunity

DOI:  https://doi.org/10.1172/JCI167359
Am J Pathol. 2023 Jul 06. pii: S0002-9440(23)00237-7. [Epub ahead of print]

Stress and Liver Fibrogenesis: Understanding the role and regulation of stress response pathways in Hepatic Stellate Cells.

Zachary Hanquier, Jagannath Misra, Reese Baxter, Jessica L Maiers.

  Stress response pathways are crucial for cells to adapt to physiological and pathological conditions. Increased transcription and translation in response to stimuli places a strain on the cell, necessitating increased amino acid supply, protein production and folding, and disposal of misfolded proteins. Stress response pathways such as the Unfolded Protein Response (UPR) and the Integrated Stress Response (ISR) allow cells to adapt to stress and restore homeostasis; however, their role and regulation in pathological conditions such as hepatic fibrogenesis are unclear. Liver injury promotes fibrogenesis through activation of hepatic stellate cells (HSCs), which produce and secrete fibrogenic proteins to promote tissue repair. This process is exacerbated in chronic liver disease, leading to fibrosis and, if unchecked, cirrhosis. Fibrogenic HSCs exhibit activation of both the UPR and ISR, due in part to increased transcriptional and translational demands, and these stress responses play important roles in fibrogenesis. Targeting these pathways to limit fibrogenesis or promote HSC apoptosis are potential anti-fibrotic strategies, but are limited by our lack of mechanistic understanding of how the UPR and ISR regulate HSC activation and fibrogenesis. In this article we explore the role of the UPR and ISR in the progression of fibrogenesis and highlight areas that require further investigation to better understand how the UPR and ISR can be targeted to limit hepatic fibrosis progression.

Keywords:  ATF6α; Cirrhosis; Endoplasmic Reticulum; GCN2; HRI; IRE1α; Integrated Stress Response; PERK; PRK; Unfolded Protein Response

DOI:  https://doi.org/10.1016/j.ajpath.2023.06.006
Semin Liver Dis. 2023 Jul 14.

Role of endoplasmic reticulum stress response in liver regeneration.

Kshitij Deshmukh, Udayan Apte.

Exposure to hepatotoxic chemicals is involved in liver disease-related morbidity and mortality worldwide. The liver responds to damage by triggering compensatory hepatic regeneration. Physical agent or chemical-induced liver damage disrupts hepatocyte proteostasis, including endoplasmic reticulum (ER) homeostasis. Post liver injury ER experiences a homeostatic imbalance, followed by active ER stress response signaling. Activated ER stress response causes selective upregulation of stress response genes and downregulation of many hepatocyte genes. Acetaminophen overdose, CCl4, acute and chronic alcohol exposure, and physical injury activates the ER stress response, but details about the cellular consequences of the ER stress response on liver regeneration remain unclear. The current data indicate that inhibiting the ER stress response after partial hepatectomy-induced liver damage promotes liver regeneration, whereas inhibiting the ER stress response after chemical-induced hepatotoxicity impairs liver regeneration. This review summarizes key findings and emphasizes the knowledge gaps in role of ER stress in injury and regeneration.

DOI: https://doi.org/10.1055/a-2129-8977
Nat Commun. 2023 07 11. 14(1): 4119

Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity.

Jessica D Rosarda, Sarah Giles, Sarah Harkins-Perry, Elizabeth A Mills, Martin Friedlander, R Luke Wiseman, Kevin T Eade.

The accumulation of atypical, cytotoxic 1-deoxysphingolipids (1-dSLs) has been linked to retinal diseases such as diabetic retinopathy and Macular Telangiectasia Type 2. However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remain poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define biological pathways that modulate 1-dSL toxicity in human retinal organoids. Our results demonstrate that 1-dSLs differentially activate signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Müller glia. Using a combination of pharmacologic activators and inhibitors, we show that sustained PERK signaling through the integrated stress response (ISR) and deficiencies in signaling through the protective ATF6 arm of the UPR are implicated in 1-dSL-induced photoreceptor toxicity. Further, we demonstrate that pharmacologic activation of ATF6 mitigates 1-dSL toxicity without impacting PERK/ISR signaling. Collectively, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different arms of the UPR.

DOI: https://doi.org/10.1038/s41467-023-39775-w
Mol Cell. 2023 Jun 29. pii: S1097-2765(23)00467-7. [Epub ahead of print]

Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2.

Vibhu Prasad, Berati Cerikan, Yannick Stahl, Katja Kopp, Vera Magg, Nelson Acosta-Rivero, Heeyoung Kim, Katja Klein, Charlotta Funaya, Uta Haselmann, Mirko Cortese, Florian Heigwer, Josephine Bageritz, David Bitto, Saruul Jargalsaikhan, Christopher Neufeldt, Felix Pahmeier, Michael Boutros, Yohei Yamauchi, Alessia Ruggieri, Ralf Bartenschlager.

  Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remodels the endoplasmic reticulum (ER) to form replication organelles, leading to ER stress and unfolded protein response (UPR). However, the role of specific UPR pathways in infection remains unclear. Here, we found that SARS-CoV-2 infection causes marginal activation of signaling sensor IRE1α leading to its phosphorylation, clustering in the form of dense ER-membrane rearrangements with embedded membrane openings, and XBP1 splicing. By investigating the factors regulated by IRE1α-XBP1 during SARS-CoV-2 infection, we identified stress-activated kinase NUAK2 as a novel host-dependency factor for SARS-CoV-2, HCoV-229E, and MERS-CoV entry. Reducing NUAK2 abundance or kinase activity impaired SARS-CoV-2 particle binding and internalization by decreasing cell surface levels of viral receptors and viral trafficking likely by modulating the actin cytoskeleton. IRE1α-dependent NUAK2 levels were elevated in SARS-CoV-2-infected and bystander non-infected cells, promoting viral spread by maintaining ACE2 cell surface levels and facilitating virion binding to bystander cells.

Keywords:  ACE2; CLEM; IRE1a ultrastructure; SARS-CoV-2; TMPRSS2; coronavirus; membrane dynamics; trafficking; unfolded protein response; virus entry

DOI:  https://doi.org/10.1016/j.molcel.2023.06.020
Cell Rep. 2023 Jul 07. pii: S2211-1247(23)00757-X. [Epub ahead of print]42(7): 112746

Marchf6 E3 ubiquitin ligase critically regulates endoplasmic reticulum stress, ferroptosis, and metabolic homeostasis in POMC neurons.

Sang-Hyeon Mun, Chang-Seok Lee, Hyun Jin Kim, Jiye Kim, Haena Lee, Jihye Yang, Sin-Hyeog Im, Joung-Hun Kim, Je Kyung Seong, Cheol-Sang Hwang.

  The metabolic prohormone pro-opiomelanocortin (POMC) is generally translocated into the endoplasmic reticulum (ER) for entry into the secretory pathway. Patients with mutations within the signal peptide (SP) of POMC or its adjoining segment develop metabolic disorders. However, the existence, metabolic fate, and functional outcomes of cytosol-retained POMC remain unclear. Here, we show that SP-uncleaved POMC is produced in the cytosol of POMC neuronal cells, thus inducing ER stress and ferroptotic cell death. Mechanistically, the cytosol-retained POMC sequesters the chaperone Hspa5 and subsequently accelerates degradation of the glutathione peroxidase Gpx4, a core regulator of ferroptosis, via the chaperone-mediated autophagy. We also show that the Marchf6 E3 ubiquitin ligase mediates the degradation of cytosol-retained POMC, thereby preventing ER stress and ferroptosis. Furthermore, POMC-Cre-mediated Marchf6-deficient mice exhibit hyperphagia, reduced energy expenditure, and weight gain. These findings suggest that Marchf6 is a critical regulator of ER stress, ferroptosis, and metabolic homeostasis in POMC neurons.

Keywords:  CP: Cell biology; CP: Metabolism; Gpx4; Hspa5; Marchf6; endoplasmic reticulum stress; ferroptosis; hyperphagia; pro-opiomelanocortin; ubiquitin ligase; weight gain

DOI:  https://doi.org/10.1016/j.celrep.2023.112746
Front Med (Lausanne). 2023 ;10 1124514

Inhibition of protein translation under matrix-deprivation stress in breast cancer cells.

Shweta Warrier, Shivaani Srinivasan, Adithya Chedere, Annapoorni Rangarajan.

  Matrix-deprivation stress leads to cell-death by anoikis, whereas overcoming anoikis is critical for cancer metastasis. Work from our lab and others has identified a crucial role for the cellular energy sensor AMPK in anoikis-resistance, highlighting a key role for metabolic reprogramming in stress survival. Protein synthesis is a major energy-consuming process that is tightly regulated under stress. Although an increase in protein synthesis in AMPK-depleted experimentally-transformed MEFs has been associated with anoikis, the status and regulation of protein translation in epithelial-origin cancer cells facing matrix-detachment remains largely unknown. Our study shows that protein translation is mechanistically abrogated at both initiation and elongation stages by the activation of the unfolded protein response (UPR) pathway and inactivation of elongation factor eEF2, respectively. Additionally, we show inhibition of the mTORC1 pathway known for regulation of canonical protein synthesis. We further functionally assay this inhibition using SUnSET assay, which demonstrates repression of global protein synthesis in MDA-MB-231 and MCF7 breast cancer cells when subjected to matrix-deprivation. In order to gauge the translational status of matrix-deprived cancer cells, we undertook polysome profiling. Our data revealed reduced but continuous mRNA translation under matrix-deprivation stress. An integrated analysis of transcriptomic and proteomic data further identifies novel targets that may aid cellular adaptations to matrix-deprivation stress and can be explored for therapeutic intervention.

Keywords:  ISR; SUnSET; mTORC1; matrix-deprivation; polysome; protein translation; stress; translatome

DOI:  https://doi.org/10.3389/fmed.2023.1124514