Physiological Caspase Substrates in Apoptosis

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Caspases process close to 1000 substrates, some of which when cleaved are critical for the characteristic morphological and molecular changes associated with apoptosis. Some well-established substrates of apoptotic caspases are listed below, including one of the first identified substrates, PARP-1.

Mammalian Caspase

Function

Cleavage Outcome

BID	Pro-apoptotic protein that regulate outer mitochondrial membrane permeability	Functional Gain	Post-proteolytic N-myristoylation results in targeting to the mitochondria and release of cytochrome c
Gelsolin	Calcium regulated actin binding protein, regulates actin filament assembly and disassembly	Functional Gain	De-polymerization of F-actin and leads to membrane blebbing
ICAD	Binds and prevents activation of the CAD nuclease (DFF40)	Functional Loss	Inhibition of DNA replication and fragmentation
Lamin B1	Involved in nuclear stability, chromatin structure	Functional Loss	Nuclear fragmentation, apoptotic bodies
PARP	Catalyzes poly(ADP-ribose) transfer from NAD+ to acceptor proteins, including itself, in response to DNA strand breaks	Functional Loss	Suppressed stability of DNA-PKcs and impaired DNA strand breaks repair
PAK2	Small GTPase-activated serine/threonine kinase involved in several cytoskeletal functions	Functional Gain	Cytoskeletal reorganization and membrane blebbing
RB	Tumor suppressor that inhibits cell cycle progression into S-phase by inhibiting transcription from E2F promoters	Functional Loss	Results in unopposed E2F-1 action and reduced antiapoptotic activity
ROCK1	Serine/threonine kinase which is cleaved by Caspase-3. Cleavage removes an autoinhibitory region to form constitutively active ROCK1	Functional Gain	Phosphorylation of myosin light changes and leads to membrane blebbing

Physiological Caspase Inhibitors

Caspase activity is inhibited by several families of proteins, including cellular FLICE-like inhibitory protein (cFLIP) and the Inhibitors of Apoptosis (IAP) family. cFLIP prevents activation of Caspase-8 and -10 by competing for binding to DISC. IAPs are characterized structurally by the presence of one or three BIR (Baculovirus IAP) domains and act as caspase inhibitors by several mechanisms, including direct caspase binding. Eight IAPs have been identified in humans and some, such as the cIAPs, are ubiquitin ligases, targeting multiple proteins for proteasomal degradation. Not surprisingly, elevated levels of cFLIP and IAPs have been detected in cancers.

Domain Organization of the IAP Family

Caspase inhibitors and the Inhibitors of Apoptosis

AIP Domains:- BIR: Baculoviral IAP repeat; CARD: Caspase activation and recruitment domains; RING: Really interesting new gene; UBC: Ubiquitin-conjugating

Learn More About Apoptosis Signaling