ARTS
(Sept4_i2) is a mitochondrial pro-apoptotic protein. ARTS induces apoptosis by
binding and antagonizing XIAP. ARTS expression is frequently lost in leukemia, lymphoma and
liver cancer (hepatocellular carcinoma) patients, indicating that it functions as a tumor suppressor
protein. Evidence for the role of ARTS
as tumor suppressor has come from inactivation of the mouse Sept4 gene,
which encodes ARTS. Sept4/ARTS-null mice show accelerated tumor development, elevated XIAP levels and have stem cells with increased resistance to cell
death, demonstrating a physiological role of ARTS for regulating XIAP levels
and apoptosis in vivo.
B-cell lymphoma 2 (Bcl-2)
protein inhibits apoptosis. We have found that ARTS
and Bcl-2 both reside at the outer mitochondrial membrane and bind to each
other in living cells. Upon induction of apoptosis, ARTS recruits XIAP and acts
as a scaffold to bring it into a complex with Bcl-2. This induced proximity
allows XIAP, but not cIAP1, Siah, or Parkin to function as the E3-ligase
promoting degradation of Bcl-2. Ubiquitination of Bcl-2 is significantly
inhibited in ARTS knock-down (ARTS KD) cells, and levels of Bcl-2 remain high
upon staurosporine and etoposide treatment in these cells. Moreover, primary and
stable MEFs from Sept4/ARTS knock-out (KO) mice and ARTS KD cells all have
reduced Bcl-2 ubiquitination and maintain high levels of Bcl-2 upon induction
of apoptosis, indicating that ARTS is required for Bcl-2 down-regulation in
vivo. Collectively, these results suggest that ARTS acts as a novel Bcl-2
antagonist to initiate apoptosis.
