Neisseria meningitidisporin PorB interacts with mitochondria and protects cells from apoptosis

Abstract

Neisserial porins are strong immune adjuvants and B cell activators. The effect of neisserial porin PorB on activation-induced cell death was investigated, as a potential additional mechanism of the porin's immunopotentiating ability. Neisserial porins interact with target cells to localize intracellularly in the mitochondrial compartment without negatively affecting cellular survival. Pretreatment with Neisseria meningitidis PorB porin decreased or abrogated the mitochondrial damage induced by apoptotic stimuli. In addition, end stage determinants of apoptosis, including DNA breakdown, were diminished by PorB. Immunoprecipitation experiments revealed that PorB interacts with the mitochondrial porin VDAC (voltage-dependent anion channel). The mechanism of the antiapoptotic effect of neisserial porins could be explained by the proteinprotein interaction of PorB with VDAC, similar to the interaction of VDAC with antiapoptotic Bcl-2 proteins, resulting in an enhancement of cell survival and continued activation of B cells.cell death ͉ voltage-dependent anion channel (VDAC) ͉ membrane potential ͉ staurosporine N eisserial porins, meningococcal PorA (class 1 protein) or PorB (class 2 or 3 proteins) or gonococcal protein IA or protein IB, are the major outer membrane protein of the pathogenic Neisseriaceae (1). They act as pores and are essential for organism survival. Interestingly, we and other investigators have demonstrated that these proteins act as immune stimulants and adjuvants (2-4) and can induce a T cell-dependent immune response against cell independent antigens (5-8). The mechanism of the adjuvant activity of neisserial porins recently has been elucidated, correlating with the porins' ability to upregulate the expression of the costimulatory molecule, B7-2, on the surface of B cells (and possibly other antigen-presenting cells) (6,8). Moreover, neisserial porins are potent B cell mitogens and act synergistically with CD40 or B cell receptor ligation to induce B cell proliferation and Ig secretion (6, 9). † Stimulation of immune cells normally increases their susceptibility to activation-induced cell death or apoptosis (10). Neisserial porins activate B cells as a probable mechanism of their adjuvant activity. If the porins also increased the susceptibility of B cells to apoptosis, this obviously would attenuate their immunopotentiating ability. Therefore, we investigated the ability of neisserial porins to affect the susceptibility of various cell types to apoptosis to determine whether another mechanism of the porins' adjuvant activity is to prevent B cell (and͞or antigen-presenting cell) apoptosis.If neisserial porins decreased the susceptibility of immune cells to apoptosis, what could be the possible mechanisms? It has been demonstrated that mitochondria and mitochondrial factors are intimately connected to the process of apoptosis (11). The mechanism of action of certain apoptotic stimuli, such as Fas receptor ligation or drugs like staurosporine (STS), involves opening of the mitochondrial permeabil...

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Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

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The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal

“…VDAC is the target of apoptosis regulatory proteins such as hepatitis virus X protein (proapopotic) (Rahmani et al, 2000) and Neisseria mengintidis porin B (anti-apoptotic) (Massari et al, 2000). ANT, conversely, appears to be the target of viral protein R (Vpr, pro-apoptotic) and vMIA/UL37 from cytomegalovirus (antiapoptotic) (Goldmacher et al, 1999).…”