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Bim and Bmf synergize to induce apoptosis in Neisseria gonorrhoeae infection.

Kepp O, Gottschalk K, Churin Y, Rajalingam K, Brinkmann V, Machuy N, Kroemer G, Rudel T - PLoS Pathog. (2009)

Bottom Line: Depletion and inhibition of Rac-1, JNK-1, Bim, or Bmf prevented the activation of Bak and Bax and the subsequent activation of caspases.Apoptosis could be reconstituted in Bim-depleted and Bmf-depleted cells by additional silencing of antiapoptotic Mcl-1 and Bcl-X(L), respectively.Our data indicate a synergistic role for both cytoskeletal-associated BH3-only proteins, Bim, and Bmf, in an apoptotic pathway leading to the clearance of Ngo-infected cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.

ABSTRACT
Bcl-2 family proteins including the pro-apoptotic BH3-only proteins are central regulators of apoptotic cell death. Here we show by a focused siRNA miniscreen that the synergistic action of the BH3-only proteins Bim and Bmf is required for apoptosis induced by infection with Neisseria gonorrhoeae (Ngo). While Bim and Bmf were associated with the cytoskeleton of healthy cells, they both were released upon Ngo infection. Loss of Bim and Bmf from the cytoskeleton fraction required the activation of Jun-N-terminal kinase-1 (JNK-1), which in turn depended on Rac-1. Depletion and inhibition of Rac-1, JNK-1, Bim, or Bmf prevented the activation of Bak and Bax and the subsequent activation of caspases. Apoptosis could be reconstituted in Bim-depleted and Bmf-depleted cells by additional silencing of antiapoptotic Mcl-1 and Bcl-X(L), respectively. Our data indicate a synergistic role for both cytoskeletal-associated BH3-only proteins, Bim, and Bmf, in an apoptotic pathway leading to the clearance of Ngo-infected cells.

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Model of Bim-dependent and Bmf-dependent apoptosis during Ngo-induced apoptosis.Ngo infection leads to a Rac-dependent activation of JNK-1 and a concurrent alteration of the cytoskeletal morphology. Upon JNK-1–mediated phosphorylation, the cytoskeleton-attached proapoptotic proteins Bim and Bmf are released. Subsequently, the antiapoptotic effects of Mcl-1 and Bcl-XL are abrogated by Bim and Bmf, respectively, leading to the activation of Bak and Bax and cell death.
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ppat-1000348-g006: Model of Bim-dependent and Bmf-dependent apoptosis during Ngo-induced apoptosis.Ngo infection leads to a Rac-dependent activation of JNK-1 and a concurrent alteration of the cytoskeletal morphology. Upon JNK-1–mediated phosphorylation, the cytoskeleton-attached proapoptotic proteins Bim and Bmf are released. Subsequently, the antiapoptotic effects of Mcl-1 and Bcl-XL are abrogated by Bim and Bmf, respectively, leading to the activation of Bak and Bax and cell death.

Mentions: The exact mode of BH3-only activity is still being discussed. Here we show that both Bim and Bmf are essential to induce Bak and Bax activity for Ngo-triggered apoptosis. As the double knockdown of Bim and Mcl-1 re-sensitized cells for apoptosis, the action of Bmf alone seems to trigger apoptosis efficiently in the absence of Mcl-1. Likewise, apoptosis could be rescued in the absence of Bmf by co-knockdown of Bcl-XL, suggesting that the action of Bim alone suffices to induced apoptosis in the absence of Bcl-XL. In this scenario, both Bim and Bmf need to be activated for efficient induction of cell death due to their joint capacity to inhibit two different anti-apoptotic Bcl-2 homologues (see model in Figure 6). As a result, this study furnishes yet another example for the complex relationship between antagonizing pro- and antiapoptotic Bcl-2 family proteins.


Bim and Bmf synergize to induce apoptosis in Neisseria gonorrhoeae infection.

Kepp O, Gottschalk K, Churin Y, Rajalingam K, Brinkmann V, Machuy N, Kroemer G, Rudel T - PLoS Pathog. (2009)

Model of Bim-dependent and Bmf-dependent apoptosis during Ngo-induced apoptosis.Ngo infection leads to a Rac-dependent activation of JNK-1 and a concurrent alteration of the cytoskeletal morphology. Upon JNK-1–mediated phosphorylation, the cytoskeleton-attached proapoptotic proteins Bim and Bmf are released. Subsequently, the antiapoptotic effects of Mcl-1 and Bcl-XL are abrogated by Bim and Bmf, respectively, leading to the activation of Bak and Bax and cell death.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654407&req=5

ppat-1000348-g006: Model of Bim-dependent and Bmf-dependent apoptosis during Ngo-induced apoptosis.Ngo infection leads to a Rac-dependent activation of JNK-1 and a concurrent alteration of the cytoskeletal morphology. Upon JNK-1–mediated phosphorylation, the cytoskeleton-attached proapoptotic proteins Bim and Bmf are released. Subsequently, the antiapoptotic effects of Mcl-1 and Bcl-XL are abrogated by Bim and Bmf, respectively, leading to the activation of Bak and Bax and cell death.
Mentions: The exact mode of BH3-only activity is still being discussed. Here we show that both Bim and Bmf are essential to induce Bak and Bax activity for Ngo-triggered apoptosis. As the double knockdown of Bim and Mcl-1 re-sensitized cells for apoptosis, the action of Bmf alone seems to trigger apoptosis efficiently in the absence of Mcl-1. Likewise, apoptosis could be rescued in the absence of Bmf by co-knockdown of Bcl-XL, suggesting that the action of Bim alone suffices to induced apoptosis in the absence of Bcl-XL. In this scenario, both Bim and Bmf need to be activated for efficient induction of cell death due to their joint capacity to inhibit two different anti-apoptotic Bcl-2 homologues (see model in Figure 6). As a result, this study furnishes yet another example for the complex relationship between antagonizing pro- and antiapoptotic Bcl-2 family proteins.

Bottom Line: Depletion and inhibition of Rac-1, JNK-1, Bim, or Bmf prevented the activation of Bak and Bax and the subsequent activation of caspases.Apoptosis could be reconstituted in Bim-depleted and Bmf-depleted cells by additional silencing of antiapoptotic Mcl-1 and Bcl-X(L), respectively.Our data indicate a synergistic role for both cytoskeletal-associated BH3-only proteins, Bim, and Bmf, in an apoptotic pathway leading to the clearance of Ngo-infected cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.

ABSTRACT
Bcl-2 family proteins including the pro-apoptotic BH3-only proteins are central regulators of apoptotic cell death. Here we show by a focused siRNA miniscreen that the synergistic action of the BH3-only proteins Bim and Bmf is required for apoptosis induced by infection with Neisseria gonorrhoeae (Ngo). While Bim and Bmf were associated with the cytoskeleton of healthy cells, they both were released upon Ngo infection. Loss of Bim and Bmf from the cytoskeleton fraction required the activation of Jun-N-terminal kinase-1 (JNK-1), which in turn depended on Rac-1. Depletion and inhibition of Rac-1, JNK-1, Bim, or Bmf prevented the activation of Bak and Bax and the subsequent activation of caspases. Apoptosis could be reconstituted in Bim-depleted and Bmf-depleted cells by additional silencing of antiapoptotic Mcl-1 and Bcl-X(L), respectively. Our data indicate a synergistic role for both cytoskeletal-associated BH3-only proteins, Bim, and Bmf, in an apoptotic pathway leading to the clearance of Ngo-infected cells.

Show MeSH
Related in: MedlinePlus