Caspase-1

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Introduction

Caspases are a unique family of cysteine proteases involved in inflammation and apoptosis. They are highly conserved and can be divided into two groups based on their apoptotic or inflammatory capacity. The "inflammation" subfamily includes human caspases 1, 4, 5, and 12 and murine caspases 1, 11, and 12. The clustering of inflammatory caspase genes to the same chromosomal locus (human 11q22.1, mouse 9A1) supports the hypothesis that gene duplication leads to caspase variability. By participating in the activation of pro-inflammatory cytokines proIL-1β and proIL-18, inflammatory caspases play a key role in the innate immune responses. The prototype cysteine protease caspase-1 was first described as an IL-1β converting enzyme, and later identified as a cysteine protease. procaspase-1 has an N-terminal caspase activation and recruitment domain (CARD), a large domain (p20) containing a large catalytic subunit (active site), and a short C-terminal domain (p10), the three domains are separated by a linker sequence. Procaspase-1 needs to undergo autoproteolytic and then form a caspase-1 heterotetramer to have sufficient catalytic activity. The crystal structure analysis shows that active caspase-1 is a tetramer structure composed of two symmetrically arranged p20/p10 dimers. One p20/p10 dimer communicates with another dimer through a set of hydrogen bonds and hydrophobic interactions. It is generally believed that the activation of the inflammasome/caspase-1 pathway solely feature pro-inflammatory functions. However, now there is more and more evidence that caspase-1 can also accomplish anti-inflammatory tasks. In addition, enzymatically-deficient caspase-1 can be used as a pro-inflammatory scaffold, and rare occurring human CASP1 variants with reduced or absent of enzyme activity are associated with recurrent febrile episodes.

Pro-inflammatory functions of caspase-1

Caspase-1 is known for the proteolytical cleavage of proIL-1β and proIL-18 into their mature forms (Figure 1). These cytokines lack a signaling peptide, and their secretion is achieved through a unique "unconventional protein secretion" pathway which is independent of the ER/Golgi pathway, and usually requires caspase-1 expression and enzymatic activation. Nowadays, caspase-1-dependent cell death is known as pyroptosis, which is a programmed pro-inflammatory cell death independent of apoptotic caspases. Pyroptosis is characterized by an increase in cell size, followed by rupture of the cytoplasmic membrane, and the leakage of endogenous DAMPs such as ATP, HMGB1 or IL-1α. In addition, caspase-1 promotes pro-inflammatory signal transduction through NF-κB activation: first, caspase-1 mediated IL-1β secretion leads to activation of IL-1 receptor, and then NF-κB activation. Second, caspase-1-dependent cleavage of Myd88 adapter-like induces TLR2- and TLR4-mediated NF-κB activation. Caspase-1 proteolytically activates caspase-7, and the subsequent release of PARP1 from chromatin enhances the expression of NF-κB-dependent genes. Then, the CARD-CARD domain interaction between procaspase-1 and receptor-interacting protein kinase 2 (RIP2) leads to NF-κB activation. Although there are different interactions between procaspase-1 and RIP2 or ASC, ASC guides procaspase-1 away from RIP2, thereby inhibiting NF-κB activation and at the same time inducing inflammasome-mediated IL-1β production.

Figure 1. Pro- and anti-inflammatory functions of caspase-1(Winkler, S.; Rösen-Wolff, A. 2015)

Defective caspase-1 facilitates autoinflammation

Naturally occurring caspase-1 variants were detected in a population of patients with autoinflammatory syndrome-like symptoms who excluded genetic alterations of MEFV, NLRP3, MVK, or PSTPIP1 genes, as well as autoantibodies or classical rheumatic disease, and a total of 7 genetic variants of caspase-1 were found, some of which were heterozygous, compound heterozygous or homozygous, some of which occurred

heterozygously, compound-heterozygously, or homozygously. Almost all relatives of patients with or without procaspase-1 variants were immunological healthy, thus excluding a monogenetic disorder with high penetrance. However, the incidence of the variants in patients is higher than that in healthy donors, this phenomenon supports the hypothesis that procaspase-1 variants are disease-promoting factors. The study of Lamkanfi et al. showed that the activation of NF-κB by procaspase-1 independently with its enzyme activity. The underlying mechanism may be similar to the activation of NF-κB mediated in response to the binding of RIP2 to nucleotide binding oligomerization domain-containing protein (NOD2). Interestingly, the interaction between the enzymatically inactive procaspase-1 variant and RIP2 is significantly enhanced compared to wild-type procaspase-1. In addition, the expression of wild-type procaspase-1 induces the cleavage of RIP2 and mediates the release of RIP2 into the cell culture supernatant, thereby reducing the intracellular level of RIP2. Loss of this regulatory mechanism or enhanced procaspase-1/RIP2 interaction in procaspase-1 variants may increase inflammation in predisposed patients, leading to autoinflammatory reactions and clinical symptoms of inflammation.

Figure 2. Defective caspase-1 provokes inflammation (Winkler, S.; Rösen-Wolff, A. 2015)