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

Sidrauski, Carmela; Tsai, Jordan C.; Kampmann, Martin; Hearn, Brian R.; Vedantham, P.; Jaishankar, Priyadarshini; Sokabe, Masaaki; Mendez, Aaron S; Newton, Billy W.; Tang, Edward L; Verschueren, Erik; Johnson, Jeffrey R.; Krogan, Nevan J.; Fraser, Christopher S.; Weissman, Jonathan S.; Renslo, Adam R.; Walter, Peter

doi:10.7554/elife.07314

Cited by 220 publications

(253 citation statements)

References 57 publications

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“…Therefore, we tested whether the eIF2␣-induced translational inhibition was involved in the regulation of these inflammatory genes using the recently described compound ISRIB (26). This compound reverses the translational block brought on by phosphorylation of eIF2␣ through an agonistic effect on EIF2B (27). As expected, ISRIB suppressed thapsigargin-induced ATF4 protein expression, had no effect on ATF4 mRNA, and modestly reduced CHOP mRNA (Fig.…”

Section: Inflammatory Gene Expression Is Dependent On the Phosphoeif2mentioning

confidence: 71%

Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses

Guthrie

Abiraman

Plyler

et al. 2016

Journal of Biological Chemistry

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Inflammation and endoplasmic reticulum (ER) stress are associated with many neurological diseases. ER stress is brought on by the accumulation of misfolded proteins in the ER, which leads to activation of the unfolded protein response (UPR), a conserved pathway that transmits signals to restore homeostasis or eliminate the irreparably damaged cell. We provide evidence that inhibition or genetic haploinsufficiency of protein kinase R-like endoplasmic reticulum kinase (PERK) can selectively control inflammation brought on by ER stress without impinging on UPR-dependent survival and adaptive responses or normal immune responses. Using astrocytes lacking one or both alleles of PERK or the PERK inhibitor GSK2606414, we demonstrate that PERK haploinsufficiency or partial inhibition led to reduced ER stress-induced inflammation (IL-6, CCL2, and CCL20 expression) without compromising prosurvival responses. In contrast, complete loss of PERK blocked canonical PERKdependent UPR genes and promoted apoptosis. Reversal of eIF2␣-mediated translational repression using ISRIB potently suppressed PERK-dependent inflammatory gene expression, indicating that the selective modulation of inflammatory gene expression by PERK inhibition may be linked to attenuation of eIF2␣ phosphorylation and reveals a previously unknown link between translational repression and transcription of inflammatory genes. Additionally, ER-stressed astrocytes can drive an inflammatory M1-like phenotype in microglia, and this can be attenuated with inhibition of PERK. Importantly, targeting PERK neither disrupted normal cytokine signaling in astrocytes or microglia nor impaired macrophage phagocytosis or T cell polarization. Collectively, this work suggests that targeting PERK may provide a means for selective immunoregulation in the context of ER stress without disrupting normal immune function.

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Section: Inflammatory Gene Expression Is Dependent On the Phosphoeif2mentioning

confidence: 71%

Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses

Guthrie

Abiraman

Plyler

et al. 2016

Journal of Biological Chemistry

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“…4B). Significantly, the ISR inhibitor ISRIB, a drug that stabilizes eIF2B dimers to render cells insensitive to eIF2α phosphorylation (Sidrauski et al 2015), prevented invasiveness arising from glutamine limitation (Fig. 4C).…”

Section: Inhibition Of Eif2b Drives Invasivenessmentioning

confidence: 95%

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

et al. 2017

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The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood. Here we show that microenvironmental cues, including inflammationmediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4-high/MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with anti-PD-1 immunotherapy resistance. Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity and invasion and determine therapeutic outcome.

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“…It is therefore likely that sustained ISR activation may account for some of the metabolic deregulations associated with the use of HIV-PIs in patients. In this context, ISRIB, a small molecule that potently inhibits the effects of eIF2α phosphorylation (60)(61)(62), could become an interesting therapeutic option to alleviate ISR-associated metabolic alterations in HIV-PI-treated patients.…”

Section: Discussionmentioning

confidence: 99%

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Gassart

Bujisic

Zaffalon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses.

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

Cited by 220 publications

References 57 publications

Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses

Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

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