title: The apoptogenic toxin AIP56 is a metalloprotease A-B toxin that cleaves NF-κb P65.
abstract: 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 Cys(39)-Glu(40) peptide bond and that the C-terminal domain is involved in binding and internalization into the cytosol.
authors.affiliation: Fish Immunology and Vaccinology, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Silva
authors.forename: Liliana M G
authors.initials: LM
authors.lastname: Pereira
authors.forename: Ana R
authors.initials: AR
authors.lastname: Moreira
authors.forename: Frederico
authors.initials: F
authors.lastname: Ferreira-da-Silva
authors.forename: Rui M
authors.initials: RM
authors.lastname: Brito
authors.forename: Tiago Q
authors.initials: TQ
authors.lastname: Faria
authors.forename: Irene
authors.initials: I
authors.lastname: Zornetta
authors.forename: Cesare
authors.initials: C
authors.lastname: Montecucco
authors.forename: Pedro
authors.initials: P
authors.lastname: Oliveira
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Azevedo
authors.forename: Pedro J B
authors.initials: PJ
authors.lastname: Pereira
authors.forename: Sandra
authors.initials: S
authors.lastname: Macedo-Ribeiro
authors.forename: Ana
authors.initials: A
authors.lastname: do Vale
authors.forename: Nuno M S
authors.initials: NM
authors.lastname: dos Santos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001427:Bacterial Toxins / Q000378:metabolism*; D001492:Bass; D005393:Fish Diseases / Q000378:metabolism; D054884:Host-Pathogen Interactions; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D045726:Metalloproteases / Q000378:metabolism*; D010776:Photobacterium / Q000378:metabolism*; D011994:Recombinant Proteins; D051996:Transcription Factor RelA / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D037521:Virulence Factors; D045726:Metalloproteases