Caspase-2 Substrates: To Apoptosis, Cell Cycle Control, and Beyond

Abstract

Caspase-2 belongs to the caspase family of proteins responsible for essential cellular functions including apoptosis and inflammation. Uniquely, caspase-2 has been identified as a tumor suppressor, but how it regulates this function is still unknown. For many years, caspase-2 has been considered an "orphan" caspase because, although it is able to induce apoptosis, there is an abundance of conflicting evidence that questions its necessity for apoptosis. Recent evidence supports that caspase-2 has non-apoptotic functions in the cell cycle and protection from genomic instability. It is unclear how caspase-2 regulates these opposing functions, which has made the mechanism of tumor suppression by caspase-2 difficult to determine. As a protease, caspase-2 likely exerts its functions by proteolytic cleavage of cellular substrates. This review highlights the known substrates of caspase-2 with a special focus on their functional relevance to caspase-2's role as a tumor suppressor.

Keywords: BID; MDM2; PIDD; Raidd; apoptosis; caspase-2; cell cycle; tumor suppressor.

FIGURE 1

The caspase-2 PIDDosome. The PIDDosome is the best characterized caspase-2 activation platform. PIDD-CC and RAIDD form the scaffold for complex formation via an interaction between their corresponding death domains (DD, blue squares). The CARD of caspase-2 binds the CARD of RAIDD (orange squares), promoting proximity-induced dimerization of caspase-2 monomers. This allows caspase-2 to become fully catalytically active.

FIGURE 2

BID, Golgin-160, and MDM2 are established caspase-2 substrates. The potential downstream functions of caspase-2-mediated cleavage of these substrates are shown. Cleavage of BID (left panel) promotes permeabilization of the outer mitochondrial membrane, releasing cytochrome c and activating downstream executioner caspases inducing apoptosis. Cleavage of Golgin-160 (center panel) induces Golgi fragmentation during apoptosis. MDM2 cleavage by caspase-2 (right panel) leads to the stabilization of p53 and promotion of cell cycle arrest.

FIGURE 3

Regulation of caspase-2 expression, activity, and localization. Substrate selection by caspase-2 could be directed by (A) transcriptional regulation: E2F family transcription factors both activate (E2F1) and repress (E2F7 and E2F8) caspase-2 transcription. TCF4 and SREBP2 activate caspase-2 transcription; (B) phosphorylation: Caspase-2 is phosphorylated on multiple residues. The known phosphorylation events of caspase-2 result in its inhibition, which can be regulated by metabolism (top) and the cell cycle (bottom); (C) differential activation platform assembly: The canonical PIDDosome contains both PIDD1 and RAIDD. Caspase-2 can be activated by complexes lacking one or both of these elements. NPM1 is required for the nucleolar activation complex; (D) subcellular localization: Caspase-2 contains a classical nuclear localization signal and it has been found outside the nucleus associated with the Golgi body and mitochondria. Activation of caspase-2 has also been observed specifically in the nucleolus induced by DNA damage, as well as more generally throughout cytoplasm induced by heat shock and microtubule disruption. Red stars represent sites where caspase-2 is expressed and yellow stars represent sites where caspase-2 is activated.