paracaspase

Paracaspases are a family of cysteine proteases related to caspases that possess a caspase-like protease domain but differ in their domain architecture and regulation. They are found in metazoans, with the best characterized member in humans being MALT1. Typical paracaspases feature an N-terminal death domain or death domain–like module that mediates protein interactions, followed by a protease domain at the C-terminus. This organization distinguishes them from classical initiator and executioner caspases in the apoptotic pathway.

Biological role: Paracaspases participate in signaling pathways that lead to activation of the transcription factor NF-κB, notably as part of the CBM complex composed of CARMA1, BCL10, and MALT1 in lymphocytes. Upon receptor engagement, the CBM complex promotes MALT1 protease activity, which contributes to NF-κB activation through proteolytic processing of negative regulators and by scaffolding interactions with downstream signaling proteins. MALT1 also has scaffold functions independent of protease activity.

Evolution and distribution: Paracaspases are conserved in vertebrates and many invertebrates and are considered part of the caspase superfamily with distinctive substrate specificity and regulation. They are generally not present in plants or fungi; their diversification across animals is associated with immune signaling architectures such as the CBM complex.

Clinical and research relevance: In humans, MALT1 is implicated in mucosa-associated lymphoid tissue lymphomas, particularly where API2–MALT1 fusion leads to constitutive signaling. MALT1 protease activity is a target for small-molecule inhibitors that are used to study inflammatory signaling and are investigated for potential therapeutic applications in autoimmunity and B-cell malignancies.