scholarly journals Mitochondrial dysfunction is signaled to the integrated stress response by OMA1, DELE1 and HRI

2019 ◽  
Author(s):  
Xiaoyan Guo ◽  
Giovanni Aviles ◽  
Yi Liu ◽  
Ruilin Tian ◽  
Bret A. Unger ◽  
...  
Keyword(s):  
Stress Response ◽  
Mitochondrial Dysfunction ◽  
Mammalian Cells ◽  
Fine Tuning ◽  
Integrated Stress Response ◽  
Inner Mitochondrial Membrane ◽  
Alternative Response ◽  
Mitochondrial Stress ◽  
Eif2α Phosphorylation ◽  
Eif2α Kinase

AbstractIn mammalian cells, mitochondrial dysfunction triggers the integrated stress response (ISR), in which eIF2α phosphorylation upregulates the transcription factor ATF4. However, how mitochondrial stress is relayed to the ISR is unknown. We found that HRI is the eIF2α kinase necessary and sufficient for this relay. Using an unbiased CRISPRi screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease, and DELE1, a little-characterized protein we found to be associated with the inner mitochondrial membrane. Mitochondrial stress stimulates the OMA1-dependent cleavage of DELE1, leading to its accumulation in the cytosol, where it interacts with HRI and activates its eIF2α kinase activity. Blockade of the OMA1-DELE1-HRI pathway is beneficial during some, but not all types of mitochondrial stress, and leads to an alternative response that induces specific molecular chaperones. Therefore, this pathway is a potential therapeutic target enabling fine-tuning of the ISR for beneficial outcomes in diseases involving mitochondrial dysfunction.

scholarly journals PKR and the Integrated Stress Response drive immunopathology caused by ADAR1 mutation

2020 ◽  
Author(s):  
Megan Maurano ◽  
Jessica M. Snyder ◽  
Caitlin Connelly ◽  
Jorge Henao-Mejia ◽  
Carmela Sidrauski ◽  
...  
Keyword(s):  
Stress Response ◽  
Negative Regulator ◽  
Human Diseases ◽  
Type I Interferons ◽  
Type I ◽  
Integrated Stress Response ◽  
Eif2α Phosphorylation ◽  
Molecule Inhibitor ◽  
Eif2α Kinase

SummaryMutations in ADAR, the gene that encodes the ADAR1 RNA deaminase, cause numerous human diseases, including Aicardi-Goutières Syndrome (AGS). ADAR1 is an essential negative regulator of the RNA sensor MDA5, and loss of ADAR1 function triggers inappropriate activation of MDA5 by self-RNAs. However, the mechanisms of MDA5-dependent disease pathogenesis in vivo remain unknown. Here, we introduce a knockin mouse that models the most common ADAR AGS mutation in humans. These Adar-mutant mice develop lethal disease that requires MDA5, the RIG-I-like receptor LGP2, type I interferons, and the eIF2α kinase PKR. We show that a small molecule inhibitor of the integrated stress response (ISR) that acts downstream of eIF2α phosphorylation prevents immunopathology and rescues the mice from mortality. These findings place PKR and the ISR as central components of immunopathology in vivo and identify new therapeutic targets for treatment of human diseases associated with the ADAR1-MDA5 axis.

scholarly journals Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ai-Ling Tian ◽  
Qi Wu ◽  
Peng Liu ◽  
Liwei Zhao ◽  
Isabelle Martins ◽  
...  
Keyword(s):  
Stress Response ◽  
Immune Responses ◽  
Initiation Factor ◽  
Integrated Stress Response ◽  
Serine Residue ◽  
Eif2α Phosphorylation ◽  
Lysosomotropic Agents ◽  
Cultured Human Cells

AbstractThe integrated stress response manifests with the phosphorylation of eukaryotic initiation factor 2α (eIF2α) on serine residue 51 and plays a major role in the adaptation of cells to endoplasmic reticulum stress in the initiation of autophagy and in the ignition of immune responses. Here, we report that lysosomotropic agents, including azithromycin, chloroquine, and hydroxychloroquine, can trigger eIF2α phosphorylation in vitro (in cultured human cells) and, as validated for hydroxychloroquine, in vivo (in mice). Cells bearing a non-phosphorylatable eIF2α mutant (S51A) failed to accumulate autophagic puncta in response to azithromycin, chloroquine, and hydroxychloroquine. Conversely, two inhibitors of eIF2α dephosphorylation, nelfinavir and salubrinal, enhanced the induction of such autophagic puncta. Altogether, these results point to the unexpected capacity of azithromycin, chloroquine, and hydroxychloroquine to elicit the integrated stress response.

scholarly journals GCN2 phosphorylation of eIF2α activates NF-κB in response to UV irradiation

2005 ◽  
Vol 385 (2) ◽  
pp. 371-380 ◽  
Author(s):  
Hao-Yuan JIANG ◽  
Ronald C. WEK
Keyword(s):  
Uv Irradiation ◽  
Mammalian Cells ◽  
Transcriptional Control ◽  
Control Cell ◽  
Nuclear Factor Κb ◽  
Initiation Factor ◽  
Α Subunit ◽  
Eif2α Phosphorylation ◽  
Eif2α Kinase ◽  
Secondary Function

In response to UV irradiation, mammalian cells elicit a gene expression programme designed to repair damage and control cell proliferation and apoptosis. Important members of this stress response include the NF-κB (nuclear factor-κB) family. However, the mechanisms by which UV irradiation activates NF-κB are not well understood. In eukaryotes, a variety of environmental stresses are recognized and remediated by a family of protein kinases that phosphorylate the α subunit of eIF2 (eukaryotic initiation factor-2). In the present study we show that NF-κB in MEF (murine embryo fibroblast) cells is activated by UV-C and UV-B irradiation through a mechanism requiring eIF2α phosphorylation. The primary eIF2α kinase in response to UV is GCN2 (general control non-derepressible-2), with PEK/PERK (pancreatic eIF2α kinase/RNA-dependent-protein-kinase-like endoplasmic-reticulum kinase) carrying out a secondary function. Our studies indicate that lowered protein synthesis accompanying eIF2α phosphorylation, combined with eIF2α kinase-independent turnover of IκBα (inhibitor of κBα), reduces the levels of IκBα in response to UV irradiation. Release of NF-κB from the inhibitory IκBα would facilitate NF-κB entry into the nucleus and targeted transcriptional control. We also find that loss of GCN2 in MEF cells significantly enhances apoptosis in response to UV exposure similar to that measured in cells deleted for the RelA/p65 subunit of NF-κB. These results demonstrate that GCN2 is central to recognition of UV stress, and that eIF2α phosphorylation provides resistance to apoptosis in response to this environmental insult.

scholarly journals Neuronal Mitochondrial Dysfunction Activates the Integrated Stress Response to Induce Fibroblast Growth Factor 21

Cell Reports ◽  
2018 ◽  
Vol 24 (6) ◽  
pp. 1407-1414 ◽  
Author(s):  
Lisa Michelle Restelli ◽  
Björn Oettinghaus ◽  
Mark Halliday ◽  
Cavit Agca ◽  
Maria Licci ◽  
...  
Keyword(s):  
Stress Response ◽  
Growth Factor ◽  
Mitochondrial Dysfunction ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Integrated Stress Response ◽  
Fibroblast Growth

scholarly journals The integrated stress response promotes B7H6 expression

2019 ◽  
Vol 98 (1) ◽  
pp. 135-148 ◽  
Author(s):  
Akram Obiedat ◽  
Yoav Charpak-Amikam ◽  
Julie Tai-Schmiedel ◽  
Einat Seidel ◽  
Mohamed Mahameed ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
List Type ◽  
Mrna Levels ◽  
Integrated Stress Response ◽  
Eif2α Phosphorylation ◽  
Car T

Abstract The B7 family member, B7H6, is a ligand for the natural killer cell receptor NKp30. B7H6 is hardly expressed on normal tissues, but undergoes upregulation on different types of tumors, implicating it as an attractive target for cancer immunotherapy. The molecular mechanisms that control B7H6 expression are poorly understood. We report that in contrast to other NK cell ligands, endoplasmic reticulum (ER) stress upregulates B7H6 mRNA levels and surface expression. B7H6 induction by ER stress requires protein kinase R-like ER kinase (PERK), one of the three canonical sensors of the unfolded protein response. PERK phosphorylates eIF2α, which regulates protein synthesis and gene expression. Because eIF2α is phosphorylated by several kinases following different stress conditions, the program downstream to eIF2α phosphorylation is called the integrated stress response (ISR). Several drugs were reported to promote the ISR. Nelfinavir and lopinavir, two clinically approved HIV protease inhibitors, promote eIF2α phosphorylation by different mechanisms. We show that nelfinavir and lopinavir sustainably instigate B7H6 expression at their pharmacologically relevant concentrations. As such, ER stress and ISR conditions sensitize melanoma targets to CAR-T cells directed against B7H6. Our study highlights a novel mechanism to induce B7H6 expression and suggests a pharmacological approach to improve B7H6-directed immunotherapy. Key messages B7H6 is induced by ER stress in a PERK-dependent mechanism. Induction of B7H6 is obtained pharmacologically by HIV protease inhibitors. Exposure of tumor cells to the HIV protease inhibitor nelfinavir improves the recognition by B7H6-directed CAR-T.

scholarly journals Heme-regulated eIF2α kinase in erythropoiesis and hemoglobinopathies

Blood ◽  
2019 ◽  
Vol 134 (20) ◽  
pp. 1697-1707 ◽  
Author(s):  
Jane-Jane Chen ◽  
Shuping Zhang
Keyword(s):  
Protein Synthesis ◽  
Stress Response ◽  
Initiation Factor ◽  
Integrated Stress Response ◽  
Iron Availability ◽  
Eukaryotic Initiation Factor ◽  
Erythroid Cells ◽  
Eif2α Kinase ◽  
In Erythroid Cells

Chen and Zhang review the role of eukaryotic initiation factor 2α (eIF2α) in regulating the balance between protein synthesis and iron availability as part of the integrated stress response in erythroid cells.

scholarly journals Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Carmela Sidrauski ◽  
Jordan C Tsai ◽  
Martin Kampmann ◽  
Brian R Hearn ◽  
Punitha Vedantham ◽  
...  
Keyword(s):  
Stress Response ◽  
Translational Control ◽  
Control Point ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Integrated Stress Response ◽  
Nucleotide Exchange ◽  
Eif2α Phosphorylation ◽  
Symmetric Molecule ◽  
Invaluable Tool

The general translation initiation factor eIF2 is a major translational control point. Multiple signaling pathways in the integrated stress response phosphorylate eIF2 serine-51, inhibiting nucleotide exchange by eIF2B. ISRIB, a potent drug-like small molecule, renders cells insensitive to eIF2α phosphorylation and enhances cognitive function in rodents by blocking long-term depression. ISRIB was identified in a phenotypic cell-based screen, and its mechanism of action remained unknown. We now report that ISRIB is an activator of eIF2B. Our reporter-based shRNA screen revealed an eIF2B requirement for ISRIB activity. Our results define ISRIB as a symmetric molecule, show ISRIB-mediated stabilization of activated eIF2B dimers, and suggest that eIF2B4 (δ-subunit) contributes to the ISRIB binding site. We also developed new ISRIB analogs, improving its EC50 to 600 pM in cell culture. By modulating eIF2B function, ISRIB promises to be an invaluable tool in proof-of-principle studies aiming to ameliorate cognitive defects resulting from neurodegenerative diseases.

The integrated stress response mediates type I interferon driven necrosis in Mycobacterium tuberculosis granulomas

2018 ◽  
Author(s):  
Bidisha Bhattacharya ◽  
Shiqi Xiao ◽  
Sujoy Chatterjee ◽  
Michael Urbanowski ◽  
Alvaro Ordonez ◽  
...  
Keyword(s):  
Stress Response ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Type I Interferon ◽  
Genetic Locus ◽  
Host Susceptibility ◽  
Type I ◽  
Integrated Stress Response ◽  
Eif2α Phosphorylation ◽  
Pathogen Survival

Necrosis in the tuberculous granuloma is a hallmark of tuberculosis that enables pathogen survival and transmission. Susceptibility to tuberculosis and several other intracellular bacteria is controlled by a mouse genetic locus, sst1, and mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung lesions, similar to human TB granulomas. Our previous work established that increased disease severity in sst1S mice reflects dysfunctional macrophage effector or tolerance mechanisms, but the molecular mechanisms have remained unclear. Here we demonstrate that sst1S macrophages develop aberrant, biphasic responses to TNF characterized by super-induction of stress and type I interferon pathways after prolonged TNF stimulation with this late-stage response being initiated by oxidative stress and Myc activation and driven via a JNK - IFNβ - PKR circuit. This circuit leads to induction of the integrated stress response (ISR) mediated by eIF2α phosphorylation and the subsequent hyper-induction of ATF3 and ISR-target genes Chac1, Trib3, Ddit4. The administration of ISRIB, a small molecule inhibitor of the ISR, blocked the development of necrosis in lung granulomas of M. tuberculosis-infected sst1S mice and concomitantly reduced the bacterial burden revealing that induction of the ISR and the locked-in state of escalating stress driven by type I IFN pathway in sst1S macrophages plays a causal role in the development of necrosis. Our data support a generalizable paradigm in intracellular pathogen-host interactions wherein host susceptibility emerges within inflammatory tissue due to imbalanced macrophage responses to growth, differentiation, activation and stress stimuli. Successful pathogens such as M. tuberculosis may exploit this aberrant response in susceptible hosts to induce necrotic lesions that favor long-term pathogen survival and transmission. Interruption of the aberrant stress response with inhibitors such as ISRIB may offer novel therapeutic strategies.

scholarly journals ATF4 helps mitochondria pass the stress test

2017 ◽  
Vol 216 (7) ◽  
pp. 1865-1865
Author(s):  
Ben Short
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Mammalian Cells ◽  
Stress Test ◽  
Mitochondrial Stress

The transcription factor ATF4 coordinates the mitochondrial stress response in mammalian cells.

scholarly journals Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals

2017 ◽  
Vol 216 (7) ◽  
pp. 2027-2045 ◽  
Author(s):  
Pedro M. Quirós ◽  
Miguel A. Prado ◽  
Nicola Zamboni ◽  
Davide D’Amico ◽  
Robert W. Williams ◽  
...  
Keyword(s):  
Stress Response ◽  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Ribosomal Proteins ◽  
Cellular Metabolism ◽  
Mitochondrial Diseases ◽  
Mitochondrial Translation ◽  
Mitochondrial Stress ◽  
Main Regulator

Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans–expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.

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