Suppressive effect of elongation factor 2 on apoptosis induced by HIV-1 viral protein R

Zelivianski, Stanislav; Dong, Liang; Chen, M.; Mirkin, Bernard L.; Zhao, Yuqi

doi:10.1007/s10495-006-4030-9

Cited by 31 publications

(39 citation statements)

References 44 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, results of this report on mdr PRs and our earlier study on the wt PR [32] suggested that mdr PR-induced cell death in fission yeast was reminiscent of PR-induced apoptosis in mammalian cells [29, 40]. This was evident by the fact that HIV-1 mdr PRs not only triggered the ROS production but also caused mitochondrial changes that were linked to apoptosis [29, 41].…”

Section: Discussionmentioning

confidence: 85%

A fission yeast cell-based system for multidrug resistant HIV-1 proteases

Benkő

Dong

et al. 2017

Cell Biosci

View full text Add to dashboard Cite

BackgroundHIV-1 protease (PR) is an essential enzyme for viral production. Thus, PR inhibitors (PIs) are the most effective class of anti-HIV drugs. However, the main challenge to the successful use of PI drugs in patient treatment is the emergence of multidrug resistant PRs (mdrPRs). This study aimed to develop a fission yeast cell-based system for rapid testing of new PIs that combat mdrPRs.ResultsThree mdrPRs were isolated from HIV-infected patients that carried seven (M7PR), ten (M10PR) and eleven (M11PR) PR gene mutations, respectively. They were cloned and expressed in fission yeast under an inducible promoter to allow the measurement of PR-specific proteolysis and drug resistance. The results showed that all three mdrPRs maintained their abilities to proteolyze HIV viral substrates (MA↓CA and p6) and to confer drug resistance. Production of these proteins in the fission yeast caused cell growth inhibition, oxidative stress and altered mitochondrial morphologies that led to cell death. Five investigational PIs were used to test the utility of the established yeast system with an FDA-approved PI drug Darunavir (DRV) as control. All six compounds suppressed the wildtype PR (wtPR) and the M7PR-mediated activities. However, none of them were able to suppress the M10PR or the M11PR.ConclusionsThe three clinically isolated mdrPRs maintained their viral proteolytic activities and drug resistance in the fission yeast. Furthermore, those viral mdrPR activities were coupled with the induction of growth inhibition and cell death, which could be used to test the PI activities. Indeed, the five investigational PIs and DRV suppressed the wtPR in fission yeast as they did in mammalian cells. Significantly, two of the high level mdrPRs (M10PR and M11PR) were resistant to all of the existing PI drugs including DRV. This observation underscores the importance of continued searching for new PIs against mdrPRs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-016-0131-5) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 85%

A fission yeast cell-based system for multidrug resistant HIV-1 proteases

Benkő

Dong

et al. 2017

Cell Biosci

View full text Add to dashboard Cite

show abstract

“…Consistent with this model, inactivating eEF-2 in other ways, such as doxorubicin-induced phosphorylation 55 or diphtheria toxin-mediated ADP ribosylation 56,57 of eEF-2, also causes cell death, whereas potentiating eEF-2 activity can protect cells from some apoptotic stimuli. 58 Therefore, eEF-2K may promote cell death during ER stress via its effect on translation elongation. With respect to the mechanistic models of eEF-2 phosphorylation induction, our results show that, in contrast to sal (discussed below), Tm induces eEF-2 phosphorylation in eIF2a A/A MEFs (Figure 4a) but not in eEF-2K À/À MEFs (Figure 3b), demonstrating that eEF-2K is necessary for this signaling event during ER stress but eIF2a phosphorylation is not.…”

Section: Discussionmentioning

confidence: 99%

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

Boyce

Ryazanov

et al. 2008

Cell Death Differ

View full text Add to dashboard Cite

Apoptosis triggered by endoplasmic reticulum (ER) stress has been implicated in many diseases but its cellular regulation remains poorly understood. Previously, we identified salubrinal (sal), a small molecule that protects cells from ER stressinduced apoptosis by selectively activating a subset of endogenous ER stress-signaling events. Here, we use sal as a probe in a proteomic approach to discover new information about the endogenous cellular response to ER stress. We show that sal induces phosphorylation of the translation elongation factor eukaryotic translation elongation factor 2 (eEF-2), an event that depends on eEF-2 kinase (eEF-2K). ER stress itself also induces eEF-2K-dependent eEF-2 phosphorylation, and this pathway promotes translational arrest and cell death in this context, identifying eEF-2K as a hitherto unknown regulator of ER stress-induced apoptosis. Finally, we use both sal and ER stress models to show that eEF-2 phosphorylation can be activated by at least two signaling mechanisms. Our work identifies eEF-2K as a new component of the ER stress response and underlines the utility of novel small molecules in discovering new cell biology. Cell Death and Differentiation (2008) 15, 589-599; doi:10.1038/sj.cdd.4402296; published online 11 January 2008 The endoplasmic reticulum (ER) serves as the primary processing site for membrane and secreted proteins. The ER recruits translating ribosomes, translocates newly synthesized polypeptides into its lumen, and promotes a variety of post-translational modifications and chaperone-facilitated protein folding. 1,2 Proper ER function is critical for numerous aspects of cell physiology, including vesicle trafficking, lipid and membrane biogenesis, and protein targeting and secretion. Accordingly, cells react rapidly to various forms of ER dysfunction -including the accumulation of unfolded, misfolded or excessive protein, ER lipid or glycolipid imbalances, or changes in the redox or ionic conditions of the ER lumenthrough a set of adaptive pathways known collectively as the ER stress response (ESR). [2][3][4][5] The ESR promotes cell survival both by increasing the capacity of the ER to fold and process client proteins and by reducing the amount of protein inside the ER. These effects are achieved through three major pathways: (1) the unfolded protein response, a transcription-dependent induction of ER lumenal chaperone proteins and many other components of the secretory apparatus, which augments the polypeptide processing capacity of the ER; 5,6 (2) the activation of proteasome-dependent ER-associated degradation to remove proteins from the ER; 7,8 and (3) the control of protein translation to modulate the polypeptide traffic into the ER. 9,10 Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger apoptosis. [11][12][13][14] ER stress and the apoptotic program coupled to it have been implicated in many important pathologies, including diabetes, obesity, neurodegenerativ...

show abstract

“…Thus, the strain that displays the highest intracellular ROS production had the lowest sensitivity towards H 2 O 2 treatment. In this context it is interesting to note that upon expression of the HIV protein Vpr in S. pombe (which, as mentioned before, causes apoptosis-like cell death) the intracellular levels of both complementing proteins hsp16 [13] and Ef2 [14] were observed to be elevated, which indicates dynamic interplay between the expression of foreign pro-apoptotic genes and endogenous anti-apoptotic responses. Similarly, an increase in the activity of endogenous ROS-defense mechanisms might be responsible for our observation that mitochondrial ROS production does not cause a significant drop in survival rates.…”

Section: Resultsmentioning

confidence: 67%

“…In this way, overexpression of fission yeast hsp16 was shown to specifically suppress Vpr induced cell death by a heat shock factor Hsf1-dependent mechanism [12,13]. Another group recently identified fission yeast elongation factor 2 (Ef2) through a genomewide search for multicopy suppressors of Vpr-induced cell death and subsequently demonstrated that overexpression of its human homologue also blocks Vpr-induced apoptosis in several mammalian cell lines [14]. As far as we know today, some mechanisms of programmed cell death are conserved between fission yeast and mammals while others are not, and we are just starting to learn for which aspects of apoptosis S. pombe can serve as a useful model.…”

Section: Introductionmentioning

confidence: 99%

ROS production by adrenodoxin does not cause apoptosis in fission yeast

et al. 2007

View full text Add to dashboard Cite

We previously showed that production of reactive oxygen species (ROS) caused by overexpression of the mitochondrial electron transfer protein adrenodoxin (Adx) induces apoptosis in mammalian cells. In the fission yeast Schizosaccharomyces pombe, ROS are also produced in cells that undergo an apoptotic-like cell death, but it is not yet clear whether they are actually causative for this phenomenon or whether they are merely produced as a by-product. Therefore, the purpose of this study was to trigger mitochondrial ROS production in fission yeast by overexpression of either wildtype Adx (Adx-WT) or of several activated Adx mutants and to investigate its consequences. It was found that strong expression of either Adx-WT or Adx-S112W did not produce any ROS, while Adx-D113Y caused a twofold and Adx1-108 a threefold increase in ROS formation as compared to basal levels. However, no typical apoptotic markers or decreased viability could be observed in these strains. Since we previously observed that an increase in mitochondrial ROS formation of about 60% above basal levels is sufficient to strongly induce apoptosis in mammalian cells, we conclude that S. pombe is either very robust to mitochondrial ROS production or does not undergo apoptotic cell death in response to mitochondrial ROS at all.

show abstract

Suppressive effect of elongation factor 2 on apoptosis induced by HIV-1 viral protein R

Cited by 31 publications

References 44 publications

A fission yeast cell-based system for multidrug resistant HIV-1 proteases

A fission yeast cell-based system for multidrug resistant HIV-1 proteases

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

ROS production by adrenodoxin does not cause apoptosis in fission yeast

Contact Info

Product

Resources

About