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Pseudomonas aeruginosa ExoT Induces Mitochondrial Apoptosis in Target Host Cells in a Manner That Depends on Its GTPase-activating Protein (GAP) Domain Activity.
Wood, Stephen J; Goldufsky, Josef W; Bello, Daniella; Masood, Sara; Shafikhani, Sasha H.
Afiliação
  • Wood SJ; From the Department of Immunology/Microbiology.
  • Goldufsky JW; From the Department of Immunology/Microbiology.
  • Bello D; From the Department of Immunology/Microbiology.
  • Masood S; From the Department of Immunology/Microbiology.
  • Shafikhani SH; From the Department of Immunology/Microbiology, Department of Internal Medicine, and Cancer Center, Rush University Medical Center, Chicago, Illinois 60612 Sasha_Shafikhani@rush.edu.
J Biol Chem ; 290(48): 29063-73, 2015 Nov 27.
Article em En | MEDLINE | ID: mdl-26451042
Pseudomonas aeruginosa is the most common cause of hospital-acquired pneumonia and a killer of immunocompromised patients. We and others have demonstrated that the type III secretion system (T3SS) effector protein ExoT plays a pivotal role in facilitating P. aeruginosa pathogenesis. ExoT possesses an N-terminal GTPase-activating protein (GAP) domain and a C-terminal ADP-ribosyltransferase (ADPRT) domain. Because it targets multiple non-overlapping cellular targets, ExoT performs several distinct virulence functions for P. aeruginosa, including induction of apoptosis in a variety of target host cells. Both the ADPRT and the GAP domain activities contribute to ExoT-induced apoptosis. The ADPRT domain of ExoT induces atypical anoikis by transforming an innocuous cellular protein, Crk, into a cytotoxin, which interferes with integrin survival signaling. However, the mechanism underlying the GAP-induced apoptosis remains unknown. In this study, we demonstrate that the GAP domain activity is both necessary and sufficient to induce mitochondrial (intrinsic) apoptosis. We show that intoxication with GAP domain results in: (i) JNK1/2 activation; (ii) substantial increases in the mitochondrial levels of activated pro-apoptotic proteins Bax and Bid, and to a lesser extent Bim; (iii) loss of mitochondrial membrane potential and cytochrome c release; and (iv) activation of initiator caspase-9 and executioner caspase-3. Further, GAP-induced apoptosis is partially mediated by JNK1/2, but it is completely dependent on caspase-9 activity. Together, the ADPRT and the GAP domains make ExoT into a highly versatile and potent cytotoxin, capable of inducing multiple forms of apoptosis in target host cells.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Infecções por Pseudomonas / Apoptose / Proteínas Ativadoras de GTPase / Proteínas Mitocondriais / Mitocôndrias Limite: Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Infecções por Pseudomonas / Apoptose / Proteínas Ativadoras de GTPase / Proteínas Mitocondriais / Mitocôndrias Limite: Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2015 Tipo de documento: Article