Department of Dermatology, University of Colorado Denver, SOM, Aurora, CO, USA
PYCARD is an adaptor protein involved in the structure and function of inflammasomes. Inflammasomes are pattern recognition receptors characteristically composed of an NLR, ASC and caspase-1 and are responsible for production of pro-inflammatory cytokines, in particular IL-1β and IL-18. There are several subtypes of inflammasomes that recognize a diverse array of microbial, endogenous, and environmental danger signals (Agostini et al., 2004; Mariathasan et al., 2004; Muruve et al., 2008; Fernandes-Alnemri et al., 2009; Hornung et al., 2009; Zhou et al., 2011; Dunn et al., 2012).
Mounting evidence indicates that inflammasomes and PYCARD also elicit non-overlapping inflammatory functions. PYCARD interaction with NLRC4 regulates both apoptosis via caspase-8 and NF-κB activation via PYD. PYCARD can inhibit or activate NF-κB through PYD interactions with the NF-κB IKK complex (Stehlik et al., 2002; Masumoto et al., 2003; Sarkar et al., 2006; Fernandes-Alnemri et al., 2007; Hasegawa et al., 2009; Hornung et al., 2009; Taxman et al., 2011).
PYCARD is also associated with inflammasome-independent transcriptional activation of cytokines and chemokines via activator protein-1 (AP-1), NF-κB, mitogen activated protein kinase (MAPK) and caspase-8 (Taxman et al., 2006). In pathogen-infected cells, PYCARD regulates MAPK phosphorylation by pathogens and Toll-like receptor (TLR) agonists via suppression of the dual-specificity phosphatase (DUSP10/MKP5), and independent of caspase-1 and IL-1β; thus demonstrating a function for ASC that is distinct from the inflammasome in modulating MAPK activity and chemokine expression (Taxman et al., 2011).
PYCARD may play an inflammasome-independent role in driving dendritic cells to stimulate T-cell priming for the induction of antigen-specific cellular and humoral immunity. Dendritic cell maturation stimuli activate caspase-1 in human dendritic cells. Inhibition of PYCARD and cathepsin B markedly diminishes the capacity of mature dendritic cells to stimulate antigen-specific T cells. The defective ability of PYCARD or cathepsin B-deficient dendritic cells to stimulate T cells is independent of inflammasome-mediated processing of inflammatory cytokines or priming of dendritic cells with pre-processed lipopolysaccharide (Guo and Dhodapkar, 2012).
On the other hand, PYCARD may also play an inflammasome-independent role in antigen-specific inflammatory disease. Mice genetically modified to lack both PYCARD alleles [ASC (-/-)] are protected from collagen-induced arthritis, whereas mice lacking Nlrp3 and caspase-1 are susceptible to collagen-induced arthritis. This may result from an inability of dendritic cells to facilitate antigen-specific activation of lymphocytes in mice lacking PYCARD. Furthermore, antigen-induced proliferation of purified T cells lacking PYCARD [ASC (-/-)] is restored upon incubation with wild type dendritic cells, but not when cultured with ASC (-/-) dendritic cells (Ippagunta et al., 2010).
Cell death (apoptosis, pyroptosis, necrosis)
PYCARD promotes caspase-mediated inhibition of cellular proliferation, DNA fragmentation and apoptosis via caspases including caspase-2/3/8 and 9 to activate the mitochondrial apoptotic pathway. The mechanism likely involves mitochondrial translocation of BAX, proteolytic maturation of BID and upregulation of the p53 response to cell stress or genotoxic insult (McConnell and Vertino, 2000; Ohtsuka et al., 2004; Hasegawa et al., 2007). PYCARD may also increase the susceptibility of leukemia cell lines to apoptotic stimuli by anticancer drugs (Masumoto et al., 1999).
PYCARD is involved in macrophage pyropoptosis (inflammatory cell death) which is characterized by potassium efflux and/or decreased intracellular potassium. The interaction of AIM2 with PYCARD leads to the formation of the pyroptosome, which induces pyroptotic cell death in response to cytoplasmic DNA in cells containing caspase-1 (Fernandes-Alnemri et al., 2007; Fernandes-Alnemri et al., 2009).
PYCARD also mediates cellular necrosis (pyronecrosis) in concert with NLRP3 and cathespin to cause programmed necrotic cell death that is independent from pyroptosis and does not require caspase-1 (Willingham et al., 2007; Satoh et al., 2013).
Jeffrey H Dunn ; Mayumi Fujita
PYCARD (PYD and CARD domain containing)
Atlas Genet Cytogenet Oncol Haematol. 2014-07-01
Online version: http://atlasgeneticsoncology.org/gene/712/pycard-(pyd-and-card-domain-containing)