Apoptosis, or programmed cell death
is a critical process for regulating cell numbers and maintaining tissue
homeostasis. Caspases, the main executioners of apoptosis are tightly regulated
by both activators and inhibitors. The best-studied family of caspase
inhibitors are the Inhibitors of Apoptosis (IAPs). In dying cells, the
inhibition of caspases by XIAP (X-linked IAP) has to be overcome to enable the
initiation of apoptosis. This is
achieved by the function of natural IAP-antagonist proteins. ARTS (Sept4_i2) is
a mitochondrial pro-apoptotic tumor suppressor protein. ARTS induces apoptosis
by binding to and inhibiting the anti-apoptotic activity of IAPs. In living cells, ARTS is localized at the
outer membrane of mitochondria. Upon induction of apoptosis, ARTS translocates
to the cytosol. This translocation occurs minutes after apoptotic induction and
precedes the release of cytochrome C and other IAP-antagonist, such as
SMAC/Diablo. Moreover, ARTS function is required for the normal “on time”
release of cytochrome C and SMAC/Diablo from mitochondria. Furthermore, we have found that ARTS binds
directly to both XIAP and Bcl-2 bringing them into a complex. ARTS-induced
proximity allows XIAP to act as an E3-ligase promoting Bcl-2 degradation. Thus,
ARTS functions as a novel Bcl-2-antagonist, and loss of ARTS can explain the
upregulation of Bcl-2 in many cancers.
Evidence for a role of ARTS as a tumor suppressor has come from both
human and mouse studies. ARTS expression is frequently lost in leukemia, lymphoma
and liver cancer (hepatocellular) carcinoma patients. In addition,
Sept4/ARTS-null mice show accelerated tumor development, and have stem cells
with increased resistance to cell death, demonstrating a physiological role of
ARTS for regulating apoptosis in vivo.
