title: The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential.
abstract: The anti-apoptotic molecule Aven was originally identified in a yeast two-hybrid screen for Bcl-x(L)-interacting proteins and has also been found to bind Apaf-1, thereby interfering with Apaf-1 self-association during apoptosome assembly. Aven is expressed in a wide variety of adult tissues and cell lines, and there is increasing evidence that its overexpression correlates with tumorigenesis, particularly in acute leukemias. The mechanism by which the anti-apoptotic activity of Aven is regulated remains poorly understood. Here we shed light on this issue by demonstrating that proteolytic removal of an inhibitory N-terminal Aven domain is necessary to activate the anti-apoptotic potential of the molecule. Furthermore, we identify Cathepsin D (CathD) as the protease responsible for Aven cleavage. On the basis of our results, we propose a model of Aven activation by which its N-terminal inhibitory domain is removed by CathD-mediated proteolysis, thereby unleashing its cytoprotective function.
authors.affiliation: Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, Frankfurt D-60596, Germany.
authors.forename: I M
authors.initials: IM
authors.lastname: Melzer
authors.forename: S B M
authors.initials: SB
authors.lastname: Fernández
authors.forename: S
authors.initials: S
authors.lastname: Bösser
authors.forename: K
authors.initials: K
authors.lastname: Lohrig
authors.forename: U
authors.initials: U
authors.lastname: Lewandrowski
authors.forename: D
authors.initials: D
authors.lastname: Wolters
authors.forename: S
authors.initials: S
authors.lastname: Kehrloesser
authors.forename: M-L
authors.initials: ML
authors.lastname: Brezniceanu
authors.forename: A C
authors.initials: AC
authors.lastname: Theos
authors.forename: P M
authors.initials: PM
authors.lastname: Irusta
authors.forename: F
authors.initials: F
authors.lastname: Impens
authors.forename: K
authors.initials: K
authors.lastname: Gevaert
authors.forename: M
authors.initials: M
authors.lastname: Zörnig
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis
chemical_list: C506592:APAF1 protein, human; C412506:AVEN protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D008565:Membrane Proteins; D002402:Cathepsin D