Is there something else besides the proapoptotic AVPI-segment in the Smac/DIABLO protein?

In mammals, apoptosis is the main mechanism to eliminate unwanted cells, securing tissue homeostasis and consequently maintaining the health in the organism. Classically, apoptosis culminates with the activation of caspases, which are enzymes that display cysteine protease activity to degrade specific substrates implied in essential cellular processes. This process is highly regulated. A key regulation mechanism is mediated by the Inhibitor of Apoptosis Proteins (IAPs) family members, which inhibit the activated forms of caspases through physical interaction with them. Smac/DIABLO, a mitochondrial protein that is translocated to the cytoplasm in apoptotic conditions, derepresses the IAP-mediated caspase inhibition through physical interaction with IAPs. The first four amino acids (AVPI) of Smac/DIABLO mediate the interaction with IAPs and subsequent apoptosis induction. This interaction has lead to the creation of small molecules mimicking the AVPI segment for potential anticancer therapy. Nevertheless, several studies have pointed out the existence of AVPI-independent functions of Smac/DIABLO. The aim of this review was to provide a landscape of these underestimated AVPI-independent biological functions that have been observed using different approaches, such as the study of endogenous splice variant isoforms and truncated and mutated artificial proteins.