Inhibition of the integrated stress response by viral proteins that block p-eIF2–eIF2B association

Rabouw, Huib H.; Visser, Lenneke de; Passchier, Tim Casper; Langereis, Martijn A.; Liu, Fan; Giansanti, Piero; Vliet, Arno L. W. van; Dekker, José G; Grein, Susanne G. van der; Saucedo, Jesús G; Anand, Aditya; Trellet, Mikaël; Bonvin, Alexandre; Walter, Peter; Heck, Albert J. R.; Groot, Raoul J. de; Kuppeveld, Frank J. M. van

doi:10.1038/s41564-020-0759-0

Cited by 44 publications

(68 citation statements)

References 56 publications

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“…Precedent for this notion comes from viruses that evolved proteins to counteract ISR mediated antiviral defenses. The AcP10 protein in the Bw-CoV SW1 virus, for example, interacts with eIF2B to exert an ISRIB-like effect, likely predisposing eIF2B to the A-state (Rabouw et al 2020). Regarding the observed changes in the ISRIB binding pocket, the newly gained structural insights can be applied 501 to engineer novel pharmacological ISR modulators that may be effective in opening new 502 therapeutic opportunities in different diseases.…”

Section: Discussionmentioning

confidence: 99%

eIF2B Conformation and Assembly State Regulate the Integrated Stress Response

Schoof

Boone

Wang

et al. 2020

Preprint

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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 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.

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Section: Discussionmentioning

confidence: 99%

eIF2B Conformation and Assembly State Regulate the Integrated Stress Response

Schoof

Boone

Wang

et al. 2020

Preprint

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“…Inhibition of polysome disassembly by cycloheximide is known to inhibit SG formation ( Mollet et al., 2008 ), and addition of cycloheximide to fasnall prevented SG formation as well ( Figures 1 D and S1 G). Next, we assessed eIF2 phosphorylation at the Ser51, a marker for arsenite-induced SGs ( Rabouw et al., 2020 ). Fasnall did not induce phosphorylation, as opposed to arsenite treatment ( Figures 1 E and S2 A).…”

Section: Resultsmentioning

confidence: 99%

Fasnall Induces Atypically Transient Stress Granules Independently of FASN Inhibition

Amen

Kaganovich

2020

iScience

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Summary Stress Granule formation has been linked to the resistance of some cancer cells to chemotherapeutic intervention. A number of studies have proposed that certain anti-tumor compounds promote cancer cell survival by inducing Stress Granule formation, leading to increased cellular fitness and apoptosis avoidance. Here we show that a potent fatty acid synthase inhibitor, fasnall, known for its anti-tumor capabilities, triggers the formation of atypical Stress Granules, independently of fatty acid synthase inhibition, characterized by high internal mobility and rapid turnover.

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“…Scale bars equal 10 μm. interaction 27 . Hence, the question comes up whether the reported in vitro antiviral effects of CQ and HCQ 27,60 are linked to their capacity to elicit the ISR, thus augmenting an innate immune response (such as the initiation of a type-1 interferon response 61,62 , beyond their action on acidophilic cellular compartments [63][64][65] .…”

Section: Discussionmentioning

confidence: 99%

“…The integrated stress response (ISR) consists in the phosphorylation of the phylogenetically conserved eukaryotic initiation factor 2α (eIF2α) by a series of eIF2α kinases (EIF2K1 to 4) and plays a cardinal role in the adaptation of stress to endoplasmic reticulum (ER) stress (in particular, the accumulation of unfolded or misfolded proteins in the ER lumen) 24 , in the innate cellular defense against viral infections (to block the translation of virusencoded RNAs into protein) [25][26][27] , as well as in the initiation of autophagy (which also can lead to the elimination of intracellular pathogens) [28][29][30][31] . Moreover, eIF2α phosphorylation contributes to the phenomenon of "immunogenic cell death" (ICD) [32][33][34] , which likely plays a major role in connecting the virus-induced death of infected cells to immune response that ultimately lead to the active elimination of virus-infected cells by cytotoxic T lymphocytes [35][36][37] .…”

Section: Introductionmentioning

confidence: 99%

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

Tian

Liu

et al. 2021

Cell Death Dis

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The 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.

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Inhibition of the integrated stress response by viral proteins that block p-eIF2–eIF2B association

Cited by 44 publications

References 56 publications

eIF2B Conformation and Assembly State Regulate the Integrated Stress Response

eIF2B Conformation and Assembly State Regulate the Integrated Stress Response

Fasnall Induces Atypically Transient Stress Granules Independently of FASN Inhibition

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

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