PYCARD

Description

The PYCARD (PYD and CARD domain containing) is a protein-coding gene located on chromosome 16.

PYCARD, often referred to as ASC (Apoptosis-associated speck-like protein containing a CARD), is a protein that in humans is encoded by the PYCARD gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen infection, however, it relocalizes rapidly to the cytoplasm, perinuclear space, endoplasmic reticulum and mitochondria and it is a key adaptor protein in activation of the inflammasome. NMR structure of full-length ASC: PDB ID 2KN6 [1]

== Function == This gene encodes an adaptor protein that is composed of two protein–protein interaction domains: a N-terminal PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD). The PYD and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the inflammatory and apoptotic signaling pathways via the activation of caspase. In normal cells, this protein is localized to the cytoplasm; however, in cells undergoing apoptosis, it forms ball-like aggregates near the nuclear periphery. PYCARD can occur in four different isoforms. Isoform 1, often referred to as canonical PYCARD, and isoform 2 are the activatory isoforms. They co-localize with nucleotide oligomerization domain-like receptors (NLRs) and caspase-1. Unlike isoform 1, isoform 2 is involved in direct IL-1β processing regulation.

PYCARD, also known as ASC (Apoptosis-associated speck-like protein containing a CARD), plays a crucial role in both apoptosis and inflammation. It promotes caspase-mediated apoptosis, primarily involving caspase-8, and also caspase-9 in a cell type-specific manner. PYCARD is involved in the activation of the mitochondrial apoptotic pathway, promoting caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types. It also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis, coupled to the activation of caspase-9, -2, and -3. In innate immunity, PYCARD functions as an adaptor protein in the assembly of various inflammasomes, including NLRP1, NLRP2, NLRP3, NLRP6, AIM2, and possibly IFI16. These inflammasomes recruit and activate caspase-1, leading to the processing and secretion of pro-inflammatory cytokines. Caspase-1-dependent inflammation results in macrophage pyroptosis, a form of cell death. The adaptor function of PYCARD in different inflammasomes is mediated by its pyrin and CARD domains and their homotypic interactions. PYCARD clusters to nucleate the formation of caspase-1 filaments through the interaction of their respective CARD domains, acting as a platform for caspase-1 polymerization. In the NLRP1 and NLRC4 inflammasomes, PYCARD is not required but facilitates the processing of procaspase-1. It collaborates with NOD2 in an inflammasome activated by bacterial muramyl dipeptide, leading to caspase-1 activation. PYCARD may also be involved in RIGI-triggered pro-inflammatory responses and inflammasome activation. In collaboration with AIM2, which detects cytosolic double-stranded DNA, PYCARD may also be involved in a caspase-1-independent cell death involving caspase-8. PYCARD is involved in the maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake. It may also be involved in the post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; this function is proposed to involve the nuclear form. PYCARD is also involved in 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. PYCARD has been shown to regulate NF-kappa-B activating and inhibiting functions. It modulates NF-kappa-B induction at the level of the IKK complex by inhibiting the kinase activity of CHUK and IKBKB. PYCARD is proposed to compete with RIPK2 for association with CASP1, thereby downregulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing. It modulates host resistance to DNA virus infection, possibly by inducing the cleavage of and inactivating CGAS in the presence of cytoplasmic double-stranded DNA.

PYCARD is also known as ASC, CARD5, TMS, TMS-1, TMS1.

Associated Diseases

WES Whole Exome Sequencing