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-XL, 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.
Highlights
Infection with various pathogens results in the inhibition or activation of apoptotic cell death [1]
We show that Neisseria gonorrhoeae (Ngo)-mediated apoptosis requires a special subset of proapoptotic proteins from the group of BH3-only proteins
In a siRNA-based miniscreen, we found Bim and Bmf, BH3-only proteins associated with the cytoskeleton, necessary to induce host cell apoptosis upon infection
Summary
Infection with various pathogens results in the inhibition or activation of apoptotic cell death [1]. Since induction of apoptosis requires the firm attachment of the gonococci to host cells [2], exfoliation of infected epithelial cells covered with adherent bacteria has been suggested as the immediate cellular responses against infection [3,4]. This detachment-associated apoptosis of infected cells resembles anoikis, a special form of apoptosis that is induced by absent or inappropriate cell–matrix interactions [5]. The antiapoptotic Bcl-2 family proteins harbor BH1-4 domains and presumably act by sequestering and inhibiting proapoptotic Bcl-2 members [8]. MOMP culminates in the release of proapoptotic proteins like cytochrome c, leading to the activation of caspases and caspase-independent death effectors [13]
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