Apoptosis‐inducing factor (AIF) inhibits protein synthesis by interacting with the eukaryotic translation initiation factor 3 subunit p44 (eIF3g)

Kim, Jong-Tae; Kim, Kwang Dong; Song, Eun Young; Lee, Hee Gu; Kim, Jae Wha; Kim, Jung Ho; Chae, Suhn-Kee; Kim, Eun‐Hee; Lee, Myeong Sok; Yang, Young; Lim, Jong‐Seok

doi:10.1016/j.febslet.2006.10.049

Cited by 29 publications

(29 citation statements)

References 40 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, our results do not exclude a role for non-nuclear proapoptotic effects of DmAIF. Indeed, mammalian AIF can exert part of its biochemical effects by arresting protein translation, through a direct interaction with eIF3g, 37 and the C. elegans AIF ortholog WAH-1 can enhance phosphatidylserine exposure of dying cells through a direct interaction with a phospholipids scramblase. 38 This means that, in different species, AIF does mediate major non-nuclear alterations in cellular physiology (protein synthesis arrest and loss of plasma membrane asymmetry) that are considered to be hallmarks of the apoptotic process, and it remains to be seen whether these changes are also influenced by DmAIF.…”

Section: Resultsmentioning

confidence: 99%

The molecular archaeology of a mitochondrial death effector: AIF in Drosophila

et al. 2008

View full text Add to dashboard Cite

Apoptosis-inducing factor (AIF) is a phylogenetically conserved redox-active flavoprotein that contributes to cell death and oxidative phosphorylation in Saccharomyces cerevisiae, Caenorhabditis elegans, mouse and humans. AIF has been characterized as a caspase-independent death effector that is activated by its translocation from mitochondria to the cytosol and nucleus. Here, we report the molecular characterization of AIF in Drosophila melanogaster, a species in which most cell deaths occur in a caspase-dependent manner. Interestingly, knockout of zygotic D. melanogaster AIF (DmAIF) expression using gene targeting resulted in decreased embryonic cell death and the persistence of differentiated neuronal cells at late embryonic stages. Although knockout embryos hatch, they undergo growth arrest at early larval stages, accompanied by mitochondrial respiratory dysfunction. Transgenic expression of DmAIF misdirected to the extramitochondrial compartment (DN-DmAIF), but not wild-type DmAIF, triggered ectopic caspase activation and cell death. DN-DmAIF-induced death was not blocked by removal of caspase activator Dark or transgenic expression of baculoviral caspase inhibitor p35, but was partially inhibited by Diap1 overexpression. Knockdown studies revealed that DN-DmAIF interacts genetically with the redox protein thioredoxin-2.In conclusion, we show that Drosophila AIF is a mitochondrial effector of cell death that plays roles in developmentally regulated cell death and normal mitochondrial function.

show abstract

Section: Resultsmentioning

confidence: 99%

The molecular archaeology of a mitochondrial death effector: AIF in Drosophila

et al. 2008

View full text Add to dashboard Cite

show abstract

“…A plausible hypothesis is that Scythe could protect AIF from degradation and perhaps favor its apoptotic action in the cytosol. Indeed, whereas the function of AIF in the nucleus is well documented (13), its action in the cytoplasm has recently emerged where it has been shown to activate caspase 7 (28). Scythe, by stabilizing and maintaining AIF in the cytosol may function as a central regulator of the action of AIF.…”

Section: Discussionmentioning

confidence: 99%

Scythe Regulates Apoptosis-inducing Factor Stability during Endoplasmic Reticulum Stress-induced Apoptosis

Desmots

Russell

Michel

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Scythe (BAT3; HLA-B associated transcript 3, Bag 6) is a protein that has been implicated in apoptosis because it can modulate the Drosophila melanogaster apoptotic regulator, Reaper. Mice lacking Scythe show pronounced defects in organogenesis and in the regulation of apoptosis and proliferation during mammalian development. However, the biochemical pathways important for Scythe function are unknown. We report here multiple levels of interaction between Scythe and the apoptogenic mitochondrial intermembrane protein AIF (apoptosis-inducing factor). Scythe physically interacts with AIF and regulates its stability. AIF stability is markedly reduced in Scythe ؊/؊ cells, which are more resistant to endoplasmic reticulum stress induced by thapsigargin. Reintroduction of Scythe or overexpression of AIF in Scythe ؊/؊ cells restores their sensitivity to apoptosis. Together, these data implicate Scythe as a regulator of AIF.Apoptosis is the physiological process responsible for the demise of superfluous, aged, damaged, and ectopic cells and is essential during embryonic development and for maintenance of adult tissue homeostasis (1). Among the numerous proteins implicated in apoptosis is Scythe (BAT3; HLA-B associated transcript; Bag 6). Scythe has been shown to interact with Reaper, a central regulator of developmental apoptosis in Drosophila melanogaster (2, 3). To date, no Reaper homologues have been discovered in vertebrate species, but Reaper and associated Drosophila regulators Hid and Grim can induce apoptosis in mammalian systems (4, 5). The interaction between Scythe and Reaper is required for Reaper-induced apoptosis in Xenopus egg extracts and results in the release of an as yet unidentified Scythe-bound apoptotic-inducing factor, leading to rapid mitochondrial cytochrome c release, caspase activation, and nuclear fragmentation. Immunodepletion of Scythe prevented reaper-induced apoptosis (2, 3). Our previous study also indicated a role for Scythe during apoptosis in a mammalian system. We found that inactivation of Scythe in the mouse resulted in lethality associated with pronounced developmental defects in the lung, kidney, and brain (6). Co-incident with organogenesis defects was widespread aberrant apoptosis and proliferation, and a resistance of Scythe-null cells to apoptosis (6).A critical step in apoptosis is often the permeabilization of mitochondrial membranes, leading to the release of proteins that are normally localized behind the outer mitochondrial membrane (7). One of those proteins is the apoptosis-inducing factor (AIF) 2 (8). In healthy cells, AIF is located in the mitochondrial intermembrane space where its physiological function is not entirely clear, but may involve protection against oxidative stress (8 -11). In apoptotic cells, AIF relocates from the mitochondria to the nucleus where it exerts its pro-apoptotic activity via chromatin condensation and large scale DNA fragmentation (12-14). Although AIF is strongly linked to apoptosis, many aspects of its activity remain to be clarified.Her...

show abstract

“…In S. cereviseae, it has been demonstrated that CypA is also essential for AIF-proapoptotic activity (13). In this eukaryote, Kim et al (27) have discovered an interaction between the N-terminus of eIF3g and the AIF C-terminal region. Through this link, AIF could regulate protein synthesis during ''programmed'' cell death (PCD).…”

Section: Aif Across the Speciesmentioning

confidence: 99%

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

et al. 2011

View full text Add to dashboard Cite

SummaryCell death has been initially divided into apoptosis, in which the cell plays an active role, and necrosis, which is considered a passive cell death program. Intense research performed in the last decades has concluded that ''programmed'' cell death (PCD) is a more complex physiological process than initially thought. Indeed, although in most cases the PCD process is achieved via a family of Cys proteases known as caspases, an important number of regulated PCD pathways do not involve this family of proteases. As a consequence, active forms of PCD are initially referred to as caspase-dependent and caspase-independent. More recent data has revealed that there are also active caspase-independent necrotic pathways defined as necroptosis (programmed necrosis). The existence of necroptotic forms of death was corroborated by the discovery of key executioners such as the kinase RIP1 or the mitochondrial protein apoptosis-inducing factor (AIF). AIF is a Janus protein with a redox activity in the mitochondria and a pro-apoptotic function in the nucleus. We have recently described a particular form of AIF-mediated caspase-independent necroptosis that also implicates other molecules such as PARP-1, calpains, Bax, Bcl-2, histone H2AX, and cyclophilin A. From a therapeutic point of view, the unraveling of this new form of PCD poses a question: is it possible to modulate this necroptotic pathway independently of the classical apoptotic paths? Because the answer is yes, a wider understanding of AIF-mediated necroptosis could theoretically pave the way for the development of new drugs that modulate PCD. To this end, we present here an overview of the current knowledge of AIF and AIF-mediated necroptosis. We also summarize the state of the art in some of the most interesting therapeutic strategies that could target AIF or the AIF-mediated necroptotic pathway.

show abstract

Apoptosis‐inducing factor (AIF) inhibits protein synthesis by interacting with the eukaryotic translation initiation factor 3 subunit p44 (eIF3g)

Cited by 29 publications

References 40 publications

The molecular archaeology of a mitochondrial death effector: AIF in Drosophila

The molecular archaeology of a mitochondrial death effector: AIF in Drosophila

Scythe Regulates Apoptosis-inducing Factor Stability during Endoplasmic Reticulum Stress-induced Apoptosis

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

Contact Info

Product

Resources

About