Caspase 1

Caspase-1, formerly called IL-1 beta converting enzyme (ICE), is a member of a family of nine cysteine proteases that specifically recognizes an aspartic acid residue in the P1 position of their substrates. Most members of this family of proteases are involved in mediating programmed cell death by promoting the cleavage of critical intracellular proteins upon apoptopic activation. Caspase-1, however, seems to be uniquely involved in participating in the inflammatory response by cleaving the precursors of IL-1 beta, IL-18, and IL-33. Indeed, the rate-limiting step in inflammation due to IL-1 beta or IL-18 is the activation of caspase-1. Inactive pro-caspase-1 is converted to an active enzyme via dimerization, followed by an autocatalytic reaction that generates an active molecule composed of two large and two small subunits.



Caspase-1 is characterized as a pro-inflammatory protease, as it is responsible for processing three inflammatory cytokines: IL-1β, IL-18, and IL-33. Several inflammatory diseases, including gout, pseudo-gout, Muckle-Wells syndrome, and familial Mediterranean fever, have all been linked to inappropriate or excessive activation of caspase-1. And caspase-1 is a key mediator of inflammation in response to pathogenderived molecules and endogenous danger signals. A member of the cysteine protease family of proteins, caspase-1 cleaves a large repertoire of substrates leading to diverse downstream activities, including cleavage of the pro-inflammatory cytokines IL-1β and IL-18, and induction of a cell death pathway termed pyroptosis. IL-1β and IL-18 are synthesized as inactive precursor proteins (pro-IL-1β and pro-IL-18). Caspase-1-mediated cleavage of these proteins results in production of the bioactive form of the cytokines, which are then secreted through an unconventional protein secretion pathway. The targets of caspase-1 which lead to cell death are less clear. Following caspase-1 activation, pores are formed in host cell membranes which disrupt ion fluxes, resulting in osmotic lysis and death of the cell.

Activation of caspase-1 occurs in response to sensing of microbial or host derived signals by NLRs and a non-NLR protein known as AIM2. The caspase-1 related NLRs can be divided into distinct groups based on the domain found at the N-terminus of each protein. Members of the NLRP subfamily contain a N-terminal pyrin domain (PYR), while the NLRC proteins contain a caspase recruitment domain (CARD) at this position. The NAIP subfamily members contain baculovirus inhibitory domains (BIR) at their N-termini. Separate from the NLRs, AIM2 is a member of the PYHIN family of proteins, and lacks both the NBD and LRR region commonly found in NLRs. Instead, this protein contains a C-terminal HIN200 domain and a N-terminal PYR domain.

Though not associated with cell death in earlier literature, caspase-1 activation is increasingly becoming associated with necrosis. In fact, caspase-1-mediated necrosis has recently been termed "pyroptosis" in numerous studies. This term captures the notion of a programmed cell death that results in inflammation. This term is widely used by researchers investigating cell death induced by numerous pathogens, including Listeria, Salmonella, Yersinia, Shigella, and Fransicella. The large number of pathogens that induce caspase-1-mediated necrosis indicates that this form of cell death is a fundamental form of microbemediated cell killing. While numerous studies using a diverse array of caspase-1 inducers have provided a clear, causative link between active caspase-1 and necrosis, the precise mechanism by which this inflammatory protease causes cell death is unclear. In most systems, caspase-1 activation is concurrent or immediately prior to the appearance of holes in an affected cell's plasma membrane, large enough to allow a broad efflux of proteins. Membrane impairment, which is reversible in early phases of LT treatment, eventually results in cell death. The membrane perturbation observed in LT-treated macrophages is similar to that observed in cells following stimulation of the potassium channel P2X7, which is also associated with caspase-1 activation and cell death. It has been established, however, that P2X7 is not involved in LT-mediated cell death. Future work will be needed to unravel the means by which caspase-1 mediates a loss of membrane integrity, and LT will likely be an indispensable tool towards dissecting necrotic cell death.


Case, Christopher Lee. Regulation of Caspase-1-associated Activities in Macrophages During Legionella pneumophila Infection. Yale University, 2011.

Muehlbauer, Stefan M. Caspase-1 controls anthrax lethal toxin-mediated cell lysis and disease progression in rodent models. Yeshiva University, 2011.