Caspase - Caspase Cascade

Caspase Cascade

Caspases are regulated at a post-translational level, ensuring that they can be rapidly activated. They are first synthesized as inactive pro-caspases, that consist of a prodomain, a small subunit and a large subunit. Initiator caspases possess a longer prodomain than the effector caspases, whose prodomain is very small. The prodomain of the initiator caspases contain domains such as a CARD domain (e.g., caspases-2 and -9) or a death effector domain (DED) (caspases-8 and -10) that enables the caspases to interact with other molecules that regulate their activation. These molecules respond to stimuli that cause the clustering of the initiator caspases. Such clustering allows them to activate automatically, so that they can proceed to activate the effector caspases.

The caspase cascade can be activated by:

• granzyme B (released by cytotoxic T lymphocytes and NK cells), which is known to activate caspase-3 and -7
• death receptors (like Fas, TRAIL receptors and TNF receptor), which can activate caspase-8 and -10
• the apoptosome (regulated by cytochrome c and the Bcl-2 family), which activates caspase-9.

Some of the final targets of caspases include:

• nuclear lamins
• ICAD/DFF45 (inhibitor of caspase activated DNase or DNA fragmentation factor 45)
• PARP (poly-ADP ribose polymerase)
• PAK2 (P 21-activated kinase 2).

The role of caspase substrate cleavage in the morphology of apoptosis is not clear. However, ICAD/DFF45 acts to restrain CAD (caspase-activated DNase). The cleavage and inactivation of ICAD/DFF45 by a caspase allows CAD to enter the nucleus and fragment the DNA, causing the characteristic 'DNA ladder' in apoptotic cells.

In 2009, Queensland researchers announced caspase 1 and 3 in macrophages are regulated by p202 (a double-stranded DNA binding protein) reducing caspase response, and AIM2 (another double-stranded DNA binding protein) increasing caspase activation.