PYCARD Gene

The PYCARD gene (PYCARD stands for "PYD And CARD Domain Containing") is a protein-coding gene localized on chromosome 16p11.2. The PYCARD gene encodes an adaptor protein (apoptosis-associated speck-like protein containing a caspase recruit domain - ASC- ), which consists of two protein-protein interaction domains:

• an N-terminal PYRIN-PAAD-DAPIN domain (PYD)

and

• a C-terminal caspase recruitment domain (CARD).

Two transcript variants encoding different isoforms were found for the PYCARD gene.

The PYD and CARD domains belong to the six-helix bundle death domain-fold superfamily, which mediates the assembly of large signaling complexes in the inflammatory and apoptotic pathways via the activation of caspases.

In normal cells, the apoptosis-associated speck-like protein containing a caspase recruit domain (ASC ) is localized in the cytoplasm; in cells undergoing apoptosis, however, it forms globular aggregates near the nuclear periphery.

The ASC protein has a function as a key mediator in apoptosis and inflammation. It promotes caspase-mediated apoptosis, in which mainly caspase-8 and also caspase-9 are involved in a probably cell type-specific manner. It is involved in the activation of the mitochondrial apoptosis pathway, promotes caspase-8-dependent proteolytic maturation of BID independent of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to the activation of caspase-9, -2 and -3.

ASC is involved in macrophage pyroptosis, a caspase-1-dependent form of cell death, and is the major component of the ASC pyroptosome, which forms upon potassium deprivation and rapidly recruits and activates caspase-1.

In the innate immune response, ASC functions as an integral adaptor in the assembly of the inflammasome, which activates caspase-1, leading to the processing and secretion of pro-inflammatory cytokines (Guan Ket al. 2015). The function as an activating adaptor in different types of inflammasomes is mediated by the pyrin and CARD domains and their homotypic interactions. Required for the recruitment of caspase-1 to inflammasomes containing certain pattern recognition receptors, such as NLRP2, NLRP3, NLRP6, AIM2 and probably IFI16 (Agostini Let al. 2004; Shen C et al. 2021).

In the NLRP1 and NLRC4 inflammasomes, the adaptor function of ASC does not appear to be required, but facilitates the processing of procaspase-1.

In cooperation with NOD2, ASC is involved in an inflammasome activated by bacterial muramyl dipeptide. This process leads to the activation of caspase-1.

In association with AIM2, a protein that recognizes cytosolic double-stranded DNA, ASC is probably also involved in caspase-1-independent cell death involving caspase-8.

In adaptive immunity, ASC may be involved in the maturation of dendritic cells to stimulate T cell immunity and in cytoskeletal remodeling coupled to chemotaxis and antigen uptake, as well as in the post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2.

It is also involved in the transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways.

Regarding the regulation of NF-kappa-B, activating and inhibitory functions have been reported. ASC modulates host resistance to DNA viral infections, probably by inducing cleavage and inactivation of CGAS in the presence of cytoplasmic double-stranded DNA (Wang Y et al. 2017).

Diseases associated with PYCARD include:

• Cinca syndrome

and

• Muckle-Wells syndrome.

Associated pathways include CLEC7A (Dectin-1) and activation of the NLRP3 inflammasome by SARS-CoV-2.

The helix bundle is a conserved protein fold consisting of several α-helices, which arrange themselves parallel or antiparallel to each other. The hydrophobic parts of the individual α-helices arrange themselves inwardly and the hydrophilic parts outwardly to create a hydrophilic surface. Inside the bundle, cofactors can be bound, for example. The 3-, 4- and 6-helix bundles are known, for example.

1. Agostini Let al. (2004) NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20:319-325.
2. Alfaro E et al. (2022) Upregulated Proteasome Subunits in COVID-19 Patients: A Link with Hypoxemia, Lymphopenia and Inflammation. Biomolecules12: 442.
3. Guan Ket al. (2015) MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked Ubiquitination via the E3 Ligase TRAF3. J Immunol 194: 4880-4890.
4. Shen C et al (2021) Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome. Cell 184:5759-5774.
5. Wang Y et al (2017) Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection. Immunity 46:393-404.