ARTS (Sept4_i2) is a pro-apoptotic and tumor suppressor protein that functions as an antagonist of X-linked IAP (Inhibitor of Apoptosis protein-XIAP) and Bcl-2 to promote apoptosis. It is generally thought that mitochondrial outer membrane permeabilization (MOMP) occurs before activation of caspases and is required for it. We have shown that ARTS initiates caspase activation upstream of MOMP.  In living cells both ARTS and Bcl-2 are localized at the outer membrane of the mitochondria. Upon induction of apoptosis ARTS and Bcl-2 accumulate in the cytosol, minutes following induction of apoptosis. ARTS binds directly to XIAP and promotes its auto-ubiquitilation and degradation by the proteasome. Binding of ARTS to XIAP allows de-repression of active caspases bound to XIAP. These caspases can now cleave substrates such as Bid (to truncated Bid-tBid) known to induce MOMP and the release of Cytochrome c and Smac/Diablo from the inner membrane space of mitochondria. In addition, ARTS binds directly to the BH3 domain in Bcl-2 enabling the formation of a ternary complex. Thus, ARTS serves as an adaptor protein that brings XIAP containing an E3-ligase activity in close proximity to Bcl-2. This induces the Ubiquitylation of lysine 17 (K17) in Bcl-2 and the degradation of Bcl-2 by the proteasome.  We propose that translocation of ARTS from the mitochondria enables direct binding and rapid degradation of both major anti-apoptotic proteins XIAP and Bcl-2 in the cytosol. This initiates the release of a first wave of active caspases (initiation phase) that can promote MOMP. The opening of pores at the outer membrane of mitochondria (MOMP) allows the subsequent release of additional mitochondrial factors, including cytochrome C and SMAC/Diablo. This in turn, leads to a second phase of caspase activation (amplification phase) including formation of the apoptosome, resulting in the final destruction of the cells.