Caspase 1

Protein coding gene in the species Homo sapiens

Caspase 1/Interleukin 1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. The two inflammatory cytokines activated by Caspase 1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

Caspase 1 is evolutionarily conserved in many eukaryotes of the Kingdom Animalia. Due to its role in the inflammatory immune response, it is highly expressed in the immune organs such as the liver, kidney, spleen, and blood (neutrophils). Following infection, the inflammatory response increases expression of Caspase 1, by a positive feedback mechanism that amplifies the response. as well as a noncatalytic Caspase Activation and Recruitment Domain (CARD) It interacts with other CARD containing proteins such as Apoptosis Associated Speck like Protein Containing a CARD (ASC) and Nod Like Receptor (NLR) Family CARD Domain Containing Protein 4 (NLRC4) through CARD CARD interactions in the formation of inflammasomes.

Caspase 1, normally in its physiologically inactive zymogen form, autoactivates when it is assembled into the filamentous inflammasome complex by autoproteolysis into the p10 and p20 subunits.

Activated Caspase 1 proteolytically cleaves pro IL 1β and pro IL 18 into their active forms, IL 1β and IL 18. The active cytokines lead to a downstream inflammatory response. It also cleaves Gasdermin D into its active form, which leads to pyroptosis. The mature cytokines themselves do not contain the necessary sorting sequences to enter the ER Golgi secretory pathway, and thus are not excreted from the cell by conventional methods. However, it is theorized that the release of these proinflammatory cytokines is not reliant on cellular rupture via pyroptosis, and is in fact, an active process. There exists evidence both for and against this hypothesis. The fact that for many cell types, the cytokines are secreted despite them showing absolutely no signs of pyroptosis, supports this hypothesis. However, some experiments show that Gasdermin D nonfunctional mutants still had normal cleavage of the cytokines but lacked the ability to secrete them, indicating pyroptosis may in fact be necessary for secretion in some way.

Following the inflammatory response, an activated Caspase 1 can induce pyroptosis, a lytic form of cell death, depending on the signal received as well as the specific inflammasome sensor domain protein that received it. Though pyroptosis may or may not be required for the full inflammatory response, the inflammatory response is fully required before pyroptosis can occur.

Caspase 1 has also been shown to induce necrosis and may also function in various developmental stages. Studies of a similar protein in mice suggest a role in the pathogenesis of Huntington's disease. Alternative splicing of the gene results in five transcript variants encoding distinct isoforms. Recent studies implicated caspase 1 in promoting CD4 T cell death and inflammation by HIV, two signature events that fuel HIV disease progression to AIDS. Caspase 1 activity has also been implicated in lysosome acidification following phagocytosis of bacteria and immune complexes.