RESUMO
Here we describe a protein product of the human septin H5/PNUTL2/CDCrel2b gene, which we call ARTS (for apoptosis-related protein in the TGF-beta signalling pathway). ARTS is expressed in many cells and acts to enhance cell death induced by TGF-beta or, to a lesser extent, by other apoptotic agents. Unlike related septin gene products, ARTS is localized to mitochondria and translocates to the nucleus when apoptosis occurs. Mutation of the P-loop of ARTS abrogates its competence to activate caspase 3 and to induce apoptosis. Taken together, these observations expand the functional attributes of septins previously described as having roles in cytokinesis and cellular morphogenesis.
Assuntos
Apoptose/fisiologia , Proteínas do Citoesqueleto/fisiologia , GTP Fosfo-Hidrolases/fisiologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Sequência de Bases , Células COS , Caspases/metabolismo , Clonagem Molecular , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/genética , Primers do DNA/genética , Ativação Enzimática , GTP Fosfo-Hidrolases/química , GTP Fosfo-Hidrolases/genética , Expressão Gênica , Humanos , Mitocôndrias/metabolismo , Dados de Sequência Molecular , Septinas , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Transfecção , Fator de Crescimento Transformador beta/fisiologiaRESUMO
ARTS (Sept4_i2) is a pro-apoptotic tumor suppressor protein that functions as an antagonist of X-linked IAP (XIAP) to promote apoptosis. It is generally thought that mitochondrial outer membrane permeabilization (MOMP) occurs before activation of caspases and is required for it. Here, we show that ARTS initiates caspase activation upstream of MOMP. In living cells, ARTS is localized to the mitochondrial outer membrane. In response to apoptotic signals, ARTS translocates rapidly to the cytosol in a caspase-independent manner, where it binds XIAP and promotes caspase activation. This translocation precedes the release of cytochrome C and SMAC/Diablo, and ARTS function is required for the normal timing of MOMP. We also show that ARTS-induced caspase activation leads to cleavage of the pro-apoptotic Bcl-2 family protein Bid, known to promote MOMP. We propose that translocation of ARTS initiates a first wave of caspase activation that can promote MOMP. This leads to the subsequent release of additional mitochondrial factors, including cytochrome C and SMAC/Diablo, which then amplifies the caspase cascade and causes apoptosis.