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The Apoptogenic Toxin AIP56 Is a Metalloprotease A-B Toxin that Cleaves NF-κb P65

2013; Public Library of Science; Volume: 9; Issue: 2 Linguagem: Inglês

10.1371/journal.ppat.1003128

1553-7374

Daniela Silva, Liliana M. G. Pereira, Ana Rita Silva Moreira, Frederico Ferreira‐da‐Silva, Rui M. M. Brito, Tiago Q. Faria, Irene Zornetta, Cesare Montecucco, Pedro Oliveira, Jorge E. Azevedo, Pedro José Barbosa Pereira, Sandra Macedo‐Ribeiro, Ana do Vale, Nuno M.S. dos Santos,

NF-κB Signaling Pathways

AIP56 (apoptosis-inducing protein of 56 kDa) is a major virulence factor of Photobacterium damselae piscicida (Phdp), a Gram-negative pathogen that causes septicemic infections, which are among the most threatening diseases in mariculture. The toxin triggers apoptosis of host macrophages and neutrophils through a process that, in vivo, culminates with secondary necrosis of the apoptotic cells contributing to the necrotic lesions observed in the diseased animals. Here, we show that AIP56 is a NF-κB p65-cleaving zinc-metalloprotease whose catalytic activity is required for the apoptogenic effect. Most of the bacterial effectors known to target NF-κB are type III secreted effectors. In contrast, we demonstrate that AIP56 is an A-B toxin capable of acting at distance, without requiring contact of the bacteria with the target cell. We also show that the N-terminal domain cleaves NF-κB at the Cys39-Glu40 peptide bond and that the C-terminal domain is involved in binding and internalization into the cytosol.