bims-unfpre 2022-07-17 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–07–17
nine papers selected by
Susan Logue, University of Manitoba

Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity.
Endoplasmic Reticulum Stress and miRNA Impairment in Aging and Age-Related Diseases.
SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1α/XBP1 ER stress pathway in human lung-derived cells.
Exosomes, autophagy and ER stress pathways in human diseases: Cross-regulation and therapeutic approaches.
Amyloid aggregates exert cell toxicity causing irreversible damages in the endoplasmic reticulum.
The clinical relevance of unfolded protein response signaling in breast cancer.
Endoplasmic reticulum oxidoreductin provides resilience against reductive stress and hypoxic conditions by mediating luminal redox dynamics.
Hijacking Cellular Stress Responses to Promote Lifespan.
The Brucella Effector BspI Suppresses Inflammation via Inhibition of IRE1 Kinase Activity during Brucella Infection.

Trends Cancer. 2022 Jul 08. pii: S2405-8033(22)00134-0. [Epub ahead of print]

Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity.

Camilla Salvagno, Jessica K Mandula, Paulo C Rodriguez, Juan R Cubillos-Ruiz.

  The tumor microenvironment (TME) provokes endoplasmic reticulum (ER) stress in malignant cells and infiltrating immune populations. Sensing and responding to ER stress is coordinated by the unfolded protein response (UPR), an integrated signaling pathway governed by three ER stress sensors: activating transcription factor (ATF6), inositol-requiring enzyme 1α (IRE1α), and protein kinase R (PKR)-like ER kinase (PERK). Persistent UPR activation modulates malignant progression, tumor growth, metastasis, and protective antitumor immunity. Hence, therapies targeting ER stress signaling can be harnessed to elicit direct tumor killing and concomitant anticancer immunity. We highlight recent findings on the role of the ER stress responses in onco-immunology, with an emphasis on genetic vulnerabilities that render tumors highly sensitive to therapeutic UPR modulation.

Keywords:  ER stress; cancer therapy; immune cells; tumor microenvironment; unfolded protein response

DOI:  https://doi.org/10.1016/j.trecan.2022.06.006
Front Aging. 2021 ;2 790702

Endoplasmic Reticulum Stress and miRNA Impairment in Aging and Age-Related Diseases.

Tugce Demirel-Yalciner, Erdi Sozen, Nesrin Kartal Ozer.

  Aging is a physiological process defined by decreased cellular and tissue functions. Reduced capacity of protein degradation is one of the important hallmarks of aging that may lead to misfolded protein accumulation and progressive loss of function in organ systems. Recognition of unfolded/misfolded protein aggregates via endoplasmic reticulum (ER) stress sensors activates an adaptive mechanism, the unfolded protein response (UPR). The initial step of UPR is defined by chaperone enhancement, ribosomal translation suppression, and misfolded protein degradation, while prolonged ER stress triggers apoptosis. MicroRNAs (miRNAs) are non-coding RNAs affecting various signaling pathways through degradation or translational inhibition of targeted mRNAs. Therefore, UPR and miRNA impairment in aging and age-related diseases is implicated in various studies. This review will highlight the recent insights in ER stress-miRNAs alterations during aging and age-related diseases, including metabolic, cardiovascular, and neurodegenerative diseases and several cancers.

Keywords:  aging; cancer; cardiovascular diseases; endoplasmic reticulum stress; metabolic disorders; microRNA; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fragi.2021.790702
bioRxiv. 2022 Jun 13. pii: 2021.12.30.474519. [Epub ahead of print]

SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1α/XBP1 ER stress pathway in human lung-derived cells.

Long C Nguyen, David M Renner, Diane Silva, Dongbo Yang, Nicholas Parenti, Kaeri M Medina, Vlad Nicolaescu, Haley Gula, Nir Drayman, Andrea Valdespino, Adil Mohamed, Christopher Dann, Kristin Wannemo, Lydia Robinson-Mailman, Alan Gonzalez, Letícia Stock, Mengrui Cao, Zeyu Qiao, Raymond E Moellering, Savas Tay, Glenn Randall, Michael F Beers, Marsha Rich Rosner, Scott A Oakes, Susan R Weiss.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available, or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed essential for viral replication. We examined the master UPR sensor IRE1α kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1α-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1α as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1α through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1α was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1α, perhaps as a strategy to eliminate detection by the host immune system.
IMPORTANCE: SARS-CoV-2 is the third lethal respiratory coronavirus after MERS-CoV and SARS-CoV to emerge this century, causing millions of deaths world-wide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease. Thus, it is imperative to understand the similarities and differences among these viruses in how each interacts with host cells. We focused here on the inositol-requiring enzyme 1α (IRE1α) pathway, part of the host unfolded protein response to virus-induced stress. We found that while MERS-CoV and HCoV-OC43 fully activate the IRE1α kinase and RNase activities, SARS-CoV-2 only partially activates IRE1α, promoting its kinase activity but not RNase activity. Based on IRE1α-dependent gene expression changes during infection, we propose that SARS-CoV-2 prevents IRE1α RNase activation as a strategy to limit detection by the host immune system.

DOI: https://doi.org/10.1101/2021.12.30.474519
Biochim Biophys Acta Mol Basis Dis. 2022 Jul 07. pii: S0925-4439(22)00155-7. [Epub ahead of print] 166484

Exosomes, autophagy and ER stress pathways in human diseases: Cross-regulation and therapeutic approaches.

Babak Jahangiri, Ali Kian Saei, Patience O Obi, Narjes Asghari, Shahrokh Lorzadeh, Shirin Hekmatirad, Marveh Rahmati, Fatemeh Velayatipour, Mohammad Hosseni Asghari, Ayesha Saleem, Mohammad Amin Moosavi.

  Exosomal release pathway and autophagy together maintain homeostasis and survival of cells under stressful conditions. Autophagy is a catabolic process through which cell entities, such as malformed biomacromolecules and damaged organelles, are degraded and recycled via the lysosomal-dependent pathway. Exosomes, a sub-type of extracellular vesicles (EVs) formed by the inward budding of multivesicular bodies (MVBs), are mostly involved in mediating communication between cells. The unfolded protein response (UPR) is an adaptive response that is activated to sustain survival in the cells faced with the endoplasmic reticulum (ER) stress through a complex network that involves protein synthesis, exosomes secretion and autophagy. Disruption of the critical crosstalk between EVs, UPR and autophagy may be implicated in various human diseases, including cancers and neurodegenerative diseases, yet the molecular mechanism(s) behind the coordination of these communication pathways remains obscure. Here, we review the available information on the mechanisms that control autophagy, ER stress and EV pathways, with the view that a better understanding of their crosstalk and balance may improve our knowledge on the pathogenesis and treatment of human diseases, where these pathways are dysregulated.

Keywords:  Autophagy; Cancer; Crosstalk; ER stress; Exosomes; Extracellular vesicles; Secretory autophagy; Unfolded protein response

DOI:  https://doi.org/10.1016/j.bbadis.2022.166484
Biochim Biophys Acta Mol Basis Dis. 2022 Jul 12. pii: S0925-4439(22)00156-9. [Epub ahead of print] 166485

Amyloid aggregates exert cell toxicity causing irreversible damages in the endoplasmic reticulum.

Mikhail Matveyenka, Stanislav Rizevsky, Dmitry Kurouski.

  Amyloid oligomers and fibrils are protein aggregates that cause an onset and progression of many neurodegenerative diseases, diabetes type 2 and systemic amyloidosis. Although a growing body of evidence shows that oligomers and fibrils trigger mitochondrial dysfunction simultaneously enhancing production of reactive oxygen species, exact mechanisms by which these protein aggregates exert their toxicities remain unclear. In this study, we used advanced microscopic and spectroscopic methods to examine topography and structure of insulin aggregates grown in the lipid-free environment, as well as in the presence of major classes of phospho- and sphingolipids. We also employed a set of molecular markers to determine the extent to which insulin aggregates induce a damage of cell endoplasmic reticulum (ER), an important cell organelle used for calcium storage, protein synthesis and folding. Our results show that insulin aggregates activate the expression of Activating Transcription Factor 6 (ATF6), a transmembrane protein that is involved in unfolded protein response (UPR) of the stressed ER. At the same time, two other ER transmembrane proteins, Inositol Requiring 1 (IRE1α) and eLF2a, the product of PKR-like ER kinase (PERK), exhibited very low expression levels. Furthermore, amyloid aggregates trigger an expression of the 78-kDa glucose-regulated protein GRP78, which is also involved in the UPR. We also observed UPR-induced expression of a proapoptotic transcription factor CHOP, which, in turn, regulates expression of caspase 3 kinase and BCL2 protein family members, including the ER localized Bax. These findings show that insulin oligomers and fibrils induce UPR-associated ER stress and ultimately fatal changes in cell homeostasis.

Keywords:  AFM-IR; Amyloids; Endoplasmic reticulum; Lipids; Unfolded protein response

DOI:  https://doi.org/10.1016/j.bbadis.2022.166485
Am J Cancer Res. 2022 ;12(6): 2627-2640

The clinical relevance of unfolded protein response signaling in breast cancer.

Masanori Oshi, Arya Mariam Roy, Shipra Gandhi, Yoshihisa Tokumaru, Li Yan, Akimitsu Yamada, Itaru Endo, Kazuaki Takabe.

Protein homeostasis regulated by the Endoplasmic Reticulum (ER) is a recognized process involved in cancer progression. ER stress activates the Unfolded Protein Response (UPR) and has been implicated in a variety of cancers. Given the role of the UPR activation in carcinogenesis, we hypothesized that UPR activation could be associated with pathological progression, higher clinical stage, and worse survival in breast cancer. A total of 4,416 breast cancer patients from multiple independent cohorts were analyzed. We defined the UPR pathway score by the degree of enrichment by Gene Set Variant Analysis and median was used to divide high vs. low score groups in each cohort. High UPR breast cancer significantly enriched not only cell proliferation-related but also other pro-cancerous gene sets consistently in both METABIC and GSE96058 cohort. Majority of UPR pathway score high cells in the bulk tumor were tumor cells compared to other cells, including stromal, T-, B-, and myeloid-cells (P<0.001). UPR score was significantly associated with advanced stage, high grade, and triple negative breast cancer (TNBC) (all P<0.001). High UPR breast cancer was associated with worse patient survival in both cohorts (all P<0.001). Among breast cancer subtype, ER-positive/HER2-negative breast cancer with high UPR was significantly associated with worse survival, but neither HER-positive nor TNBC. High UPR ER-positive/HER2-negative breast cancer was infiltrated with high level of Th1 and Th2 cells, M1 macrophage, and plasma cells. On the other hand, they were significantly infiltrated with high level of several types of stromal cells in tumor microenvironment (all P<0.001). Finally, high UPR metastatic breast cancer was also associated with worse patient survival (P=0.041). UPR signaling is associated with cancer aggressiveness, and worse survival, especially ER-positive/HER2-negative breast cancer subtype.

Keywords: Biomarker; breast cancer; gene expression; hormonal; unfolded protein response
Plant Cell. 2022 Jul 12. pii: koac202. [Epub ahead of print]

Endoplasmic reticulum oxidoreductin provides resilience against reductive stress and hypoxic conditions by mediating luminal redox dynamics.

José Manuel Ugalde, Isabel Aller, Lika Kudrjasova, Romy R Schmidt, Michelle Schlößer, Maria Homagk, Philippe Fuchs, Sophie Lichtenauer, Markus Schwarzländer, Stefanie J Müller-Schüssele, Andreas J Meyer.

Oxidative protein folding in the endoplasmic reticulum (ER) depends on the coordinated action of protein disulfide isomerases and ER oxidoreductins (EROs). Strict dependence of ERO activity on molecular oxygen as the final electron acceptor implies that oxidative protein folding and other ER processes are severely compromised under hypoxia. Here, we isolated viable Arabidopsis thaliana ero1 ero2 double mutants that are highly sensitive to reductive stress and hypoxia. To elucidate the specific redox dynamics in the ER in vivo, we expressed the glutathione redox potential (EGSH) sensor Grx1-roGFP2iL-HDEL with a midpoint potential of -240 mV in the ER of Arabidopsis plants. We found EGSH values of -241 mV in wild-type plants, which is less oxidizing than previously estimated. In the ero1 ero2 mutants, luminal EGSH was reduced further to -253 mV. Recovery to reductive ER stress induced by dithiothreitol, was delayed in ero1 ero2. The characteristic signature of EGSH dynamics in the ER lumen triggered by hypoxia was affected in ero1 ero2 reflecting a disrupted balance of reductive and oxidizing inputs, including nascent polypeptides and glutathione entry. The ER redox dynamics can now be dissected in vivo, revealing a central role of EROs as major redox integrators to promote luminal redox homeostasis.

DOI: https://doi.org/10.1093/plcell/koac202
Front Aging. 2022 ;3 860404

Hijacking Cellular Stress Responses to Promote Lifespan.

Naibedya Dutta, Gilberto Garcia, Ryo Higuchi-Sanabria.

  Organisms are constantly exposed to stress both from the external environment and internally within the cell. To maintain cellular homeostasis under different environmental and physiological conditions, cell have adapted various stress response signaling pathways, such as the heat shock response (HSR), unfolded protein responses of the mitochondria (UPRMT), and the unfolded protein response of the endoplasmic reticulum (UPRER). As cells grow older, all cellular stress responses have been shown to deteriorate, which is a major cause for the physiological consequences of aging and the development of numerous age-associated diseases. In contrast, elevated stress responses are often associated with lifespan extension and amelioration of degenerative diseases in different model organisms, including C. elegans. Activating cellular stress response pathways could be considered as an effective intervention to alleviate the burden of aging by restoring function of essential damage-clearing machinery, including the ubiquitin-proteosome system, chaperones, and autophagy. Here, we provide an overview of newly emerging concepts of these stress response pathways in healthy aging and longevity with a focus on the model organism, C. elegans.

Keywords:  C. elegans; aging; endoplasmic reticulum; heat-shock; mitochondria; stress

DOI:  https://doi.org/10.3389/fragi.2022.860404
J Immunol. 2022 Jul 15. pii: ji2200001. [Epub ahead of print]

The Brucella Effector BspI Suppresses Inflammation via Inhibition of IRE1 Kinase Activity during Brucella Infection.

Chen Li, Jingyu Wang, Wanchun Sun, Xiaofeng Liu, Jun Wang, Qisheng Peng.

Mammalian GTPase-activating proteins (GAPs) can inhibit innate immunity signaling in a spatiotemporal fashion; however, the role of bacterial GAPs in mediating innate immunity remains unknown. In this study, we show that BspI, a Brucella type IV secretion system (T4SS) effector protein, containing a GAP domain at the C terminus, negatively regulates proinflammatory responses and host protection to Brucella abotus infection in a mouse model. In macrophages, BspI inhibits the activation of inositol-requiring enzyme 1 (IRE1) kinase, but it does not inhibit activation of ATF6 and PERK. BspI suppresses induction of proinflammatory cytokines via inhibiting the activity of IRE1 kinase caused by VceC, a type IV secretion system effector protein that localizes to the endoplasmic reticulum. Ectopically expressed BspI interacts with IRE1 in HeLa cells. The inhibitory function of BspI depends on its GAP domain but not on interaction with small GTPase Ras-associated binding protein 1B (RAB1B). Collectively, these data support a model where BspI, in a GAP domain-dependent manner, inhibits activation of IRE1 to prevent proinflammatory cytokine responses.

DOI: https://doi.org/10.4049/jimmunol.2200001