Abstract 2958: ONC206, an imipridone derivative, induces cell death through activation of the integrated stress response in serous endometrial cancer in vitro

2020 ◽  
Author(s):  
Yingao Zhang ◽  
Yu Huang ◽  
Yajie Yin ◽  
Yali Fan ◽  
Katherine Tucker ◽  
...  
Keyword(s):  
Cell Death ◽  
Endometrial Cancer ◽  
Stress Response ◽  
Integrated Stress Response

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 Differential Effects of Antiretroviral Drugs on Neurons In Vitro: Roles for Oxidative Stress and Integrated Stress Response

2017 ◽  
Vol 13 (1) ◽  
pp. 64-76 ◽  
Author(s):  
Anna L. Stern ◽  
Rebecca N. Lee ◽  
Nina Panvelker ◽  
Jiean Li ◽  
Jenna Harowitz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Antiretroviral Drugs ◽  
Integrated Stress Response ◽  
Differential Effects

scholarly journals eIF2B Conformation and Assembly State Regulate the Integrated Stress Response

2020 ◽  
Author(s):  
Michael Schoof ◽  
Morgane Boone ◽  
Lan Wang ◽  
Rosalie Lawrence ◽  
Adam Frost ◽  
...  
Keyword(s):  
Stress Response ◽  
Binding Sites ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Integrated Stress Response ◽  
Nucleotide Exchange ◽  
Α Subunit ◽  
Rocking Motion

AbstractThe integrated stress response (ISR) is activated by phosphorylation of the translation initiation factor eIF2 in response to various stress conditions. Phosphorylated eIF2 (eIF2-P) inhibits eIF2’s nucleotide exchange factor eIF2B, a two-fold symmetric heterodecamer assembled from subcomplexes. Here, we monitor and manipulate eIF2B assembly in vitro and in vivo. In the absence of eIF2B’s α-subunit, the ISR is induced because unassembled eIF2B tetramer subcomplexes accumulate in cells. Upon addition of the small-molecule ISR inhibitor ISRIB, eIF2B tetramers assemble into active octamers. Surprisingly, ISRIB inhibits the ISR even in the context of fully assembled eIF2B decamers, revealing an allosteric communication between the physically distant eIF2, eIF2-P, and ISRIB binding sites. Cryo-EM structures suggest a rocking motion in eIF2B that couples these binding sites. eIF2-P binding converts eIF2B decamers into ‘conjoined tetramers’ with greatly diminished activity. Thus, ISRIB’s effects in disease models could arise from eIF2B decamer stabilization, allosteric modulation, or both.

scholarly journals eIF2B conformation and assembly state regulates the integrated stress response

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Michael Schoof ◽  
Morgane Boone ◽  
Lan Wang ◽  
Rosalie Lawrence ◽  
Adam Frost ◽  
...  
Keyword(s):  
Stress Response ◽  
Binding Sites ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Integrated Stress Response ◽  
Nucleotide Exchange ◽  
Α Subunit ◽  
Rocking Motion

The integrated stress response (ISR) is activated by phosphorylation of the translation initiation factor eIF2 in response to various stress conditions. Phosphorylated eIF2 (eIF2-P) inhibits eIF2's nucleotide exchange factor eIF2B, a two-fold symmetric heterodecamer assembled from subcomplexes. Here, we monitor and manipulate eIF2B assembly in vitro and in vivo. In the absence of eIF2B's α-subunit, the ISR is induced because unassembled eIF2B tetramer subcomplexes accumulate in cells. Upon addition of the small-molecule ISR inhibitor ISRIB, eIF2B tetramers assemble into active octamers. Surprisingly, ISRIB inhibits the ISR even in the context of fully assembled eIF2B decamers, revealing allosteric communication between the physically distant eIF2, eIF2-P, and ISRIB binding sites. Cryo-EM structures suggest a rocking motion in eIF2B that couples these binding sites. eIF2-P binding converts eIF2B decamers into 'conjoined tetramers' with diminished substrate binding and enzymatic activity. Canonical eIF2-P-driven ISR activation thus arises due to this change in eIF2B's conformational state.

scholarly journals Understanding and exploiting interactions between cellular proteostasis pathways and infectious prion proteins for therapeutic benefit

Open Biology ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 200282
Author(s):  
Unekwu M. Yakubu ◽  
Celso S. G. Catumbela ◽  
Rodrigo Morales ◽  
Kevin A. Morano
Keyword(s):  
Cell Death ◽  
Protein Folding ◽  
Stress Response ◽  
Prion Proteins ◽  
Infectious Agent ◽  
Therapeutic Benefit ◽  
Model Systems ◽  
Unfolded Protein ◽  
Mouse Lines

Several neurodegenerative diseases of humans and animals are caused by the misfolded prion protein (PrP Sc ), a self-propagating protein infectious agent that aggregates into oligomeric, fibrillar structures and leads to cell death by incompletely understood mechanisms. Work in multiple biological model systems, from simple baker's yeast to transgenic mouse lines, as well as in vitro studies, has illuminated molecular and cellular modifiers of prion disease. In this review, we focus on intersections between PrP and the proteostasis network, including unfolded protein stress response pathways and roles played by the powerful regulators of protein folding known as protein chaperones. We close with analysis of promising therapeutic avenues for treatment enabled by these studies.

scholarly journals Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

2021 ◽  
Vol 13 (4) ◽  
Author(s):  
Goetz Hartleben ◽  
Kenji Schorpp ◽  
Yun Kwon ◽  
Barbara Betz ◽  
Foivos‐Filippos Tsokanos ◽  
...  
Keyword(s):  
Cell Death ◽  
Stress Response ◽  
Cancer Cell ◽  
Integrated Stress Response ◽  
Combination Therapies ◽  
Pyrimidine Metabolism ◽  
Cancer Cell Death

scholarly journals Targeting the Integrated Stress Response Kinase GCN2 to Modulate Retroviral Integration

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5423
Author(s):  
Chloé Torres ◽  
Asja Garling ◽  
Saïd Taouji ◽  
Christina Calmels ◽  
Marie-Line Andreola ◽  
...  
Keyword(s):  
Stress Response ◽  
Cellular Protein ◽  
Integration Step ◽  
Integrated Stress Response ◽  
Hiv Integrase ◽  
Hiv Replication ◽  
Retroviral Integration ◽  
In Vitro Characterization ◽  
Viable Solution

Multiple viral targets are now available in the clinic to fight HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients due to resistance, with or without treatment-adherence glitches. Accordingly, it is important to better understand how HIV and other retroviruses replicate in order to propose alternative antiviral strategies. Recent studies have shown that multiple cellular factors are implicated during the integration step and, more specifically, that integrase can be regulated through post-translational modifications. We have shown that integrase is phosphorylated by GCN2, a cellular protein kinase of the integrated stress response, leading to a restriction of HIV replication. In addition, we found that this mechanism is conserved among other retroviruses. Accordingly, we developed an in vitro interaction assay, based on the AlphaLISA technology, to monitor the integrase-GCN2 interaction. From an initial library of 133 FDA-approved molecules, we identified nine compounds that either inhibited or stimulated the interaction between GCN2 and HIV integrase. In vitro characterization of these nine hits validated this pilot screen and demonstrated that the GCN2-integrase interaction could be a viable solution for targeting integrase out of its active site.

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