Caspasedependent

Caspase-dependent cell death refers to cell death processes that require the enzymatic activity of caspases to execute cellular dismantling. Caspases are a family of cysteine proteases produced as inactive zymogens and activated by proteolytic cleavage. In most contexts, caspase-dependent death underpins apoptosis, a tightly regulated form of programmed cell death essential for development and maintaining tissue homeostasis.

Activation occurs through two main cascades: an extrinsic pathway initiated by death receptors and an intrinsic mitochondrial pathway. In the extrinsic pathway, ligation of receptors such as Fas or TNF receptor leads to formation of the death-inducing signaling complex and activation of initiator caspase-8. Activated caspase-8 then activates executioner caspases (caspase-3, -6, -7) directly or by amplifying the signal through Bid to the mitochondrial pathway. In the intrinsic pathway, mitochondrial outer membrane permeabilization results in cytochrome c release, formation of the apoptosome with APAF1, and activation of caspase-9, which then activates the executioners. Executioner caspases cleave a broad set of substrates, including PARP1 and lamins, causing DNA fragmentation, membrane blebbing, and cell death.

Regulation of caspase-dependent death involves inhibitors such as IAPs that can block caspase activity and pro-apoptotic signals such as SMAC/DIABLO that antagonize IAPs. The balance between pro- and anti-apoptotic signals determines cell fate. In some circumstances, caspase-independent pathways or necroptosis may ensue if caspases are inhibited, illustrating the diversity of regulated cell death.

Pathological contexts include cancer, where caspase activation is often impaired, and neurodegenerative diseases, where excessive caspase activity can contribute to cell loss. Caspase activity is used as a biomarker in research and clinical settings to assess apoptosis.