Abstract
The bacterial PorB porin, an ATP-binding β-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (ΔΨm). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of β-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of ΔΨm. The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce ΔΨm loss and apoptosis, demonstrating that dissipation of ΔΨm is a requirement for cell death caused by neisserial infection.
Highlights
The genus Neisseria is comprised of the human pathogenic species N. gonorrhoeae (Ngo) and N. meningitidis, which cause gonorrhea and meningitis, respectively
PorBNgo-expressing cells stained negative for cytochrome c in the presence of BH3I-2 (Fig. 1A), suggesting that mitochondrial targeting of PorBNgo sensitizes cells for the complete release of cytochrome c upon Bak activation
We demonstrate that PorB induces the reorganization of mitochondrial cristae and sensitizes mitochondria to release cytochrome c in response to infection and BH3-only protein induced signaling pathways
Summary
The genus Neisseria is comprised of the human pathogenic species N. gonorrhoeae (Ngo) and N. meningitidis, which cause gonorrhea and meningitis, respectively. Infection by Ngo causes loss of membrane potential (DYm) across the inner mitochondrial membrane (IMM) and release of cytochrome c, which is required for activation of caspases and induction of apoptosis [5]. When expressed in host cells, PorB translocates to mitochondria and efficiently causes the breakdown of DYm, but fails to induce the release of cytochrome c and subsequent apoptosis under these conditions [6]. This suggested that PorB is required, but is not sufficient, to induce apoptosis, and that a second signal is needed to induce cytochrome c release during infection. Bim- and Bmf-initiated events may act in cooperation with mitochondrial PorB in apoptosis induction
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