Caspase recruitment domain-containing protein 8 (CARD8)

Caspase recruitment domain-containing protein 8 (CARD8) is an intracellular pattern recognition receptor that serves as a critical sensor in the innate immune system (UniProt Q9Y2G2) [1]. It is characterized by its ability to undergo constitutive autoproteolysis at a conserved FIIND domain, creating a non-covalently associated N-terminal and C-terminal fragment (PubMed: 30833774) [2]. CARD8 functions as an inflammasome sensor that detects the activity of specific proteases, such as HIV-1 protease, or the inhibition of the cytosolic enzymes DPP8 and DPP9 (Science, 2021) [3]. When DPP8/9 are inhibited by drugs like Talabostat (BXCL701), the N-terminal fragment of CARD8 is targeted for proteasomal degradation, liberating the bioactive C-terminal fragment to trigger the assembly of an inflammasome (Nature Chemical Biology, 2019) [4]. This process leads to the activation of caspase-1, the secretion of pro-inflammatory cytokines like IL-1β, and the induction of pyroptotic cell death. In therapeutic contexts, CARD8 is being explored as a target for cancer immunotherapy to enhance the immune system's ability to recognize and destroy tumor cells (ClinicalTrials.gov) [5].

Other names

TUCANCardinalNDPP1DACARKIAA0955Caspase recruitment domain protein 8Tumor up-regulated CARD-containing antagonist of CASP9

Inhibition of DPP8/9 leads to the degradation of the CARD8 N-terminus via the N-end rule pathway, releasing the bioactive C-terminal fragment which then recruits pro-caspase-1 to form an inflammasome, leading to pyroptosis (Nature Chemical Biology, 2019) [4].