Bim and Bmf Synergize To Induce Apoptosis in Neisseria Gonorrhoeae Infection

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.

Neisseria gonorrhoeae-Mediated Inhibition of Apoptotic Signalling in Polymorphonuclear Leukocytes

“…The reasons for the discrepancy are not clear but may be related to the use of different N. gonorrhoeae strains or differences in bacterial piliation and/or expression of opacity proteins. Our results also contrast with data demonstrating a proapoptotic effect of N. gonorrhoeae infection on epithelial cells (39,40,50,51), but those discrepancies may reflect the vast differences between PMNs and epithelial cells.…”

“…We also show that PMNs can be a significant source of proinflammatory cytokines and chemokines during infection, in addition to the epithelial cells which are thought to be responsible for initial PMN recruitment. Numerous studies of epithelial cells and lymphocytes have shown both pro-and antiapoptotic effects of infection with both N. gonorrhoeae (6,27,36,39,40,50,51) and the closely related N. meningitidis (17,48). However, PMN apoptosis during N. gonorrhoeae infection has not been examined as extensively (68), and it has not been explored at all with N. meningitidis.…”

“…Diverse Bcl-2 family proteins have been found to play roles in the proapoptotic (39,40) and antiapoptotic (5,6,27,36) phenotypes observed upon N. gonorrhoeae infection in epithelial cells, but the extent to which individual Bcl-2 proteins act to mediate PMN survival has not been determined. A major regulator of neutrophil survival is thought to be the antiapoptotic Mcl-1 protein (1), whose role in inhibiting apoptosis in N. gonorrhoeae-infected PMNs remains to be examined.…”

Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections

“…Bim and Bmf are associated with the cytoskeleton and are released in a Rac-1-dependent manner after gonococcal infection. 83 …”

Suppression of ERK activation in urethral epithelial cells infected with Neisseria gonorrhoeae and its isogenic minD mutant contributes to anti-apoptosis

“…The activation of three major mitogen activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK), has been implicated in the regulation of apoptosis by N. gonorrhoeae [7,8,11] in various cell types. JNK activation was proapoptotic in HeLa cells infected with N. gonorrhoeae [8].…”