Caspase 1

Caspase 1/Interleukin-1 converting enzyme is an enzyme that proteolytically cleaves other proteins, such as the precursor forms of the inflammatory cytokines interleukin 1β and interleukin 18 as well as Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a two-fold inflammation response through the cleavage and thus activation of the two inflammatory cytokines interleukin 1β and interleukin 18 as well as the initiation of pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase 1 are secreted from the cell to further induce the inflammatory response in neighboring cells.

Structure

Caspase 1 is produced as a zymogen that is cleaved into 20 kDa (p20) and 10 kDa (p10) subunits that become part of the active enzyme. Active caspase 1 contains two heterodimers of p20 and p10. It contains several catalytic domains, for cleaving cytokines and Gasdermin D, as well as a noncatalytic CARD, or caspase activation and recruitment domain. It interacts with other CARD containing protein such as PYCARD (or ASC) and NLRC4 through CARD-CARD interactions in the formation of inflammasomes.

Interactions

Activation

Caspase 1, normally in its inactive zymogen form, is activated when it is assembled into the filamentous inflammasome complex. The inflammasome complex is made up of a signal specific sensor protein such as those of the Nod-like receptor (NLR) family and the AIM-1 like receptors, an adaptor protein such as ASC (apoptosis associated Speck like protein containing a CARD), and a caspase, in this case caspase -1. In some cases, where the signaling proteins contain their own CARDs, like in NLRP1 and NLRC4, the CARD –CARD interaction is direct and the ASC adaptors are excluded from the inflammasome.

Repression

CARD only proteins (COPs) as their name implies, are proteins that only contain the non-catalytic CARDs. Owing the importance of CARD-CARD interactions in inflammasome formation, many COPs are known inhibitors of Caspase activation. For caspase 1, genes for specific COPs, ICEBERG, COP1 (ICE/Pseudo-ICE), and INCA are all found near its locus, and are thus thought to have emerged from gene duplication events and subsequent deletions of the caspase domains. Though they all interact with the inflammasomes using CARD –CARD interactions, they differ in the way they carry out their inhibitory functions as well as in their effectiveness at doing so.

For example, ICEBERG nucleates the formation of caspase -1 filaments and is thus incorporated into the filaments, but lacks the ability to inhibit the activation of inflammasomes. Instead, it is thought to inhibit caspase 1 activation by interfering with the interaction of caspase 1 with other important CARD containing proteins.

INCA, on the other hand, directly blocks inflammasome assembly by capping caspase-1 CARD oligomers, thus blocking further polymerization into the inflammasome filaments.

Similarly, some POPs (Pyrin only proteins) are also known to regulate caspase 1 activation through inhibition of inflammasome activation by binding to and blocking PYD interactions, though the exact mechanisms are not yet well established.

Function

Proteolytic Cleavage

Activated caspase 1 proteolytically cleaves the precursors of IL 1beta and IL-18 (pro-IL 1beta and pro IL18) into their active counterparts. The active cytokines lead to an inflammatory response. It also cleaves Gasdermin D into its active form, which leads to pyroptosis.

Inflammatory Response

Once matured, the cytokines initiate downstream signaling events to induce a proinflammatory response as well as to activate the expression of antiviral genes. The speed, specificity and types of response are dependent on the signal received as well as the sensor protein that received it.

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 is some evidence to back this up, mainly, the fact that for many cell types the cytokines are secreted despite there showing absolutely no signs of pyroptosis. There are however, some results that seem to directly contradict this hypothesis and the evidence: the fact that Gasdermin D nonfunctional mutants still had normal cleavage of the cytokines but lacked the ability to secrete them.

Pyroptosis Response

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. In order to induce pyroptosis, caspase 1 cleaves gasdermin D, which either directly or through some signaling cascade leads to pyroptosis, the exact mechanism is not known.

Caspase 1 has also been shown to induce cell necrosis and may function in various developmental stages. Studies of a similar protein in mouse 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.

See also

• The Proteolysis Map
• Caspase

External links

• The MEROPS online database for peptidases and their inhibitors: C14.001