VDAC2 enables BAX to mediate apoptosis and limit tumor development

Chin, Hui San; Li, Mark X.; Tan, Iris; Ninnis, Robert L; Reljić, Boris; Scicluna, Kristen; Dagley, Laura F.; Sandow, Jarrod J.; Kelly, Gemma L.; Samson, André L.; Chappaz, Stéphane; Khaw, Seong Lin; Chang, Catherine; Morokoff, Andrew; Brinkmann, Kerstin; Webb, Andrew I.; Hockings, Colin; Hall, Cathrine; Kueh, Andrew J.; Ryan, Michael; Kluck, Ruth M.; Bouillet, Philippe; Herold, Marco J.; Gray, Daniel H.D.; Huang, David C.S.; Delft, Mark F. van; Dewson, Grant

doi:10.1038/s41467-018-07309-4

Cited by 123 publications

(123 citation statements)

References 65 publications

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“…Interestingly, BAK activation of BAX may contribute significantly to BAX translocation and activation (Figs. 4 and 5g), consistent with recent genetic evidence that either BAK or VDAC2 can promote BAX translocation and activation 54 . However, contrary to previous studies 32,34 , our data provide little evidence that BAX directly contributes to BAX translocation or activation.…”

Section: Discussionsupporting

confidence: 86%

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

et al. 2020

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BAK and BAX, which drive commitment to apoptosis, are activated principally by certain BH3-only proteins that bind them and trigger major rearrangements. One crucial conformation change is exposure of their BH3 domain which allows BAK or BAX to form homodimers, and potentially to autoactivate other BAK and BAX molecules to ensure robust pore formation and cell death. Here, we test whether full-length BAK or mitochondrial BAX that are specifically activated by antibodies can then activate other BAK or BAX molecules. We found that antibody-activated BAK efficiently activated BAK as well as mitochondrial or cytosolic BAX, but antibody-activated BAX unexpectedly proved a poor activator. Notably, autoactivation by BAK involved transient interactions, as BAK and BAX molecules it activated could dissociate and homodimerize. The results suggest that BAK-driven autoactivation may play a substantial role in apoptosis, including recruitment of BAX to the mitochondria. Hence, directly targeting BAK rather than BAX may prove particularly effective in inhibiting unwanted apoptosis, or alternatively, inducing apoptosis in cancer cells.

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Section: Discussionsupporting

confidence: 86%

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

et al. 2020

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“…Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis discovered six signaling pathways (Table S2), i.e., cGMP-PKG signaling pathway, NOD-like receptor signaling pathway, calcium signaling pathway, cholesterol metabolism, necroptosis, and ferroptosis, which were influenced by SARS-CoV-2 S1 (Figure 4b). The up-regulation of VDAC1-3, three mitochondrial membrane porins involved in bioenergetic failure and cell apoptosis, [19][20] were attributable. In the presence of HEK-293T-hACE2 NPs, the imbalance of VDAC1-3 was corrected ( Figure 4c), and the number of changed proteins was reduced to thirty-one (Table S3), by which no signaling pathway was enriched by KEGG yet.…”

Section: Hek-293t Nps Prepared Using the Same Methods Had Comparablementioning

confidence: 99%

Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection

Wang

Chen

et al. 2020

Preprint

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The ongoing COVID-19 epidemic worldwide necessitates the development of novel effective agents against SARS-CoV-2. ACE2 is the main receptor of SARS-CoV-2 S1 protein and mediates viral entry into host cells. Herein, the membrane nanoparticles prepared from ACE2-rich cells are discovered with potent capacity to block SARS-CoV-2 infection. The membrane of human embryonic kidney-239T cell highly expressing ACE2 is screened to prepare nanoparticles. The nanomaterial termed HEK-293T-hACE2 NPs contains 265.1 ng mg−1 of ACE2 on the surface and acts as a bait to trap SARS-CoV-2 S1 in a dose-dependent manner, resulting in reduced recruitment of the viral ligand to host cells. Interestingly, SARS-CoV-2 S1 can translocate to the cytoplasm and affect the cell metabolism, which is also inhibited by HEK-293T-hACE2 NPs. Further studies reveal that HEK-293T-hACE2 NPs can efficiently suppress SARS-CoV-2 S pseudovirions entry into human proximal tubular cells and block viral infection with a low half maximal inhibitory concentration. Additionally, this biocompatible membrane nanomaterial is sufficient to block the adherence of SARS-CoV-2 D614G-S1 mutant to sensitive cells. Our study demonstrates a easy-to-acheive memrbane nano-antagonist for curbing SARS-CoV-2, which enriches the existing antiviral arsenal and provides new possibilities to treat COVID-19. Graphical Table of Contents

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“…Thus, at least in our model, VDAC2 is not essential for mitochondrial apoptosis. an earlier study from the same group found that although loss of VDAC2 reduced both Bax and Bak mitochondrial association, they both retained the ability to kill cells in response to an apoptotic signal 34 . Finally, Bax retrotranslocation off mitochondria also requires VDAC2 33 .…”

Section: Discussionmentioning

confidence: 92%

“…Falling within these strict criteria was the mitochondrial porin, VDAC2, which has been previously linked to Bax and Bak function [33][34][35][36] . We compared enrichment of VDAC2 in unsynchronised and mitotic cells expressing either mBidWT-BirA*, mBidS66A-BirA* or mBidG94E-BirA* (Fig.4E).…”

Section: Proximity Biotin Labelling Identifies Bid Interacting Partnementioning

confidence: 99%

BioID based proteomic analysis of the Bid interactome identifies novel proteins involved in cell cycle dependent apoptotic priming

Pedley

King

Mallikarjun

et al. 2019

Preprint

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Apoptotic priming refers to the proximity of cells to outer mitochondrial membrane permeabilisation (MOMP), the point of apoptosis commitment. Variations in priming are important for how both normal and cancer cells respond to chemotherapeutic agents. Individual cells adjust their level of priming in response to changing circumstances, such as genomic damage. How changes in apoptotic priming are dynamically coordinated by Bcl-2 proteins remains unclear. We have previously demonstrated that the Bcl-2 protein, Bid, becomes phosphorylated as cell enter mitosis, increasing priming. To understand how cells coordinate dynamic changes in priming, we have performed an unbiased proximity biotinylation (BioID) screen using Bid as bait. This identified several potential regulatory proteins outside the core Bcl-2 family. In particular we found VDAC2 to be essential for Bid phosphorylation dependent changes in apoptotic priming during mitosis. These results show the importance of dissecting the wider Bcl-2 interactome, and identify a key scaffold protein coordinating dynamic changes in single cell priming.

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VDAC2 enables BAX to mediate apoptosis and limit tumor development

Cited by 123 publications

References 65 publications

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection

BioID based proteomic analysis of the Bid interactome identifies novel proteins involved in cell cycle dependent apoptotic priming

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