Caspase 1

Caspase 1, due to evolutionary conservatism, persists in many eukaryotes of the animal kingdom . Due to its role in the inflammatory immune response, it is highly expressed in tissues and organs involved in immune defense, such as the liver , kidney , spleen, and blood ( neutrophils ) ^{[7] [8]} . After infection, the inflammatory response increases the expression of CASP1 using a positive feedback mechanism that enhances the response ^[8] .

Caspase 1 is formed as a zymogen (procaspase 1), which can then be split into subunits of 20 kDa (p20) and 10 kDa (p10), which later become part of the active enzyme. Active caspase 1 contains two heterodimers p20 and p10. Caspase includes a catalytic domain with an active site that encompasses both the p20 and p10 subunits ^[9] , as well as the non-catalytic activation domain of caspase and recruitment ( CARD ). It interacts with other proteins containing CARD domains, such as the apoptosis-associated Speck-like protein containing CARD ( ASC ) and the Nod-like receptor (NLR) NLRC4 , through CARD-CARD domain interactions, causing inflammatory reactions of many diseases ^{[ 3] [10]} .

Proteolytic cleavage

Activated caspase 1 proteolytically cleaves pro-IL-1β and pro-IL-18 into their active forms, IL-1β and IL-18. Active cytokines lead to an inflammatory response that occurs next. Caspase 1 also cleaves Hasdermin D into its active form, which leads to pyroptosis ^[10] .

Inflammatory response

After maturation, cytokines initiate subsequent signaling events to induce a pro-inflammatory response, as well as activate the expression of antiviral genes. The speed, specificity and types of response depend on the received signal, as well as on the protein of the sensor that received it. Signals that can accept firemasomes include viral double-stranded RNA , urea , free radicals, and other cell-threat signals, even by-products of other immune response pathways ^[11] .

Mature cytokines themselves do not contain the necessary sorting sequences for entering the ER-Golgi secretory pathway and, therefore, are not excreted from the cell by conventional methods. However, it is theoretically assumed that the release of these pro-inflammatory cytokines is independent of cell breakdown by pyroptosis and is actually an active process. There is evidence for and against this hypothesis. The fact that cytokines are secreted for many types of cells, despite the fact that they show absolutely no signs of pyroptosis, supports this hypothesis ^{[12] [13]} . However, some experiments show that non-functional Hasdermin D mutants still have normal cleavage of cytokines, but do not have the ability to secrete them, this indicates that pyroptosis may indeed be necessary for secretion in some way ^[14] .

Pyroptosis

After an inflammatory response, activated caspase-1 can induce pyroptosis, the lytic form of cell death, depending on the signal received, as well as on the specific domain of the inflammasome protein that received it. Although pyroptosis may or may not be required for a complete inflammatory response, an inflammatory response is completely necessary before pyroptosis occurs. In order to cause pyroptosis, caspase-1 cleaves Hasdermin D, which either directly or through some signaling cascade leads to pyroptosis ^[12] . The exact mechanism of pyroptosis is unknown ^[12] .

Other features

It has also been shown that caspase-1 causes necrosis and can also function at various stages of development. Studies of a similar protein in mice indicate a role in the pathogenesis of Huntington's disease . Alternative gene splicing leads to five transcription variants encoding various isoforms ^[15] . Recent studies have shown the involvement of caspase-1 in the promotion of death of CD4 T cells from HIV infection , two significant events that contribute to HIV progression and lead to AIDS ^{[16] [17]} .

Activation

Caspase-1, usually in its physiologically inactive form of zymogen, is activated when it is assembled into a filamentous inflammatory complex ( inflammasoma ) by autoproteolysis into the subunits p10 and p20 ^{[18] [19]} . The inflammasome is a ring complex consisting of trimers specific for protein-protein signals, such as NLR cells, and AIM-1 receptors (absent in melanoma), adapter proteins such as ASC , and caspases, in this case caspases 1. In some cases, when signaling proteins contain their own CARD domains, for example, in NLRP1 and NLRC4 , the CARD-CARD interaction is direct, that is, there is no adapter protein in the complex. There are various sensory and adapter proteins, various combinations of which give answers to inflammatory reactions to certain signals. This allows the cell to have a different concentration of inflammas depending on the severity of the received signal ^{[12] [20]} .

Inhibition

Only the CARD domain containing proteins (COP), as the name implies, are proteins that contain only non-catalytic CARD domains. Due to the importance of CARD-CARD interactions in the formation of inflammation, many COPs are known caspase activation inhibitors. For caspase-1, the genes responsible for the specific interaction of the complexes COP-ICEBERG, COP1 (ICE / pseudo-ICE) and INCA (Inhibitory CARD) are all found near the locus and are believed to have arisen from events of gene duplication and subsequent deletions of catalytic domains. Although they all interact with the inflammasome through the interaction of CARD-CARD, however, they differ in how they perform their inhibitory functions, as well as in their inhibition efficiency ^{[19] [21] [22]} .

For example, ICEBERG initiates the formation of caspase 1 filaments and, thus, is incorporated into filaments, but does not have the ability to inhibit the activation of inflammatory diseases. Instead, it is believed that it inhibits the activation of caspase-1, preventing its interaction with other important proteins containing the CARD domain ^{[19] [21] [22]} .

INCA, on the other hand, directly blocks the assembly of the inflammasome through the association (enlargement) of caspase CARD-domain oligomers, and thereby blocks the further polymerization of the inflammasome filaments ^{[10] [21] [22] [23]} .

Similarly, POP proteins act by regulating the activation of caspase-1 by inhibiting the activation of the inflammatory process by acting on the mechanism of binding and blocking of PYD interactions, which also play a role in the formation of inflammatory diseases, although the exact mechanisms have not yet been established ^{[22] [24 ] ]} .

• Caspases
• Pyroptosis
• Inflammasoma