caspase

Caspases are a family of cysteine proteases that play essential roles in programmed cell death (apoptosis) and inflammatory responses. They are synthesized as inactive zymogens, known as procaspases, which contain an N-terminal prodomain, a large catalytic subunit (p20), and a small catalytic subunit (p10). Activation occurs by proteolytic cleavage that generates an active heterotetramer composed of two p20 and two p10 subunits. Caspases are broadly categorized into initiator caspases, which sense cellular stress and begin the cascade, and executioner caspases, which dismantle cellular components.

Initiator caspases, such as caspase-8 and caspase-9, possess long prodomains with protein interaction motifs (CARD or DED) that recruit adaptor proteins FADD or Apaf-1 to form activation complexes. Executioner caspases, including caspase-3, caspase-6, and caspase-7, are activated by cleavage by initiator caspases and then cleave a wide array of substrates to drive apoptosis. In addition to apoptosis, certain caspases (notably caspase-1, and in humans caspase-4/5 and caspase-11 in mice) participate in inflammation, processing cytokines such as interleukin-1β and interleukin-18 and, in some contexts, triggering pyroptosis through gasdermin D cleavage.

Caspases have diverse roles beyond cell death, including development, differentiation, and immune regulation. Dysregulation of caspase activity is linked to cancer, neurodegenerative diseases, and inflammatory disorders. Therapeutic strategies include caspase inhibitors to modulate excessive apoptosis or inflammation, though selective targeting remains a challenge due to overlapping substrates and pathways. Prominent members include CASP3, CASP7, CASP8, CASP9, and CASP1.