![]() ![]() The PYD, also referred to as PAAD or DAPIN, is a protein binding domain belonging to the death domain superfamily ( 12). Although not as well-established and in many cases derived from overexpression studies, these proteins have also been linked to transcriptional responses, through activation of NF-κB, IRFs, and MAPKs to regulate pro-inflammatory and anti-microbial gene expression, autophagy, and to affect adaptive immune responses. ![]() Furthermore, there is increasing evidence for a broader contribution of inflammasomes to unconventional protein secretion ( 8), to lipid biogenesis and to the release of inflammatory lipids ( 9– 11). Active caspases then induce inflammatory cell death (pyroptosis), maturation, and/or secretion of the leaderless pro-inflammatory cytokines IL-1β and IL-18, and contribute to the release of the related IL-1α ( 4, 5) as well as the stress-associated danger signal HMGB1 ( 6, 7). Thus, a necessity of these PRRs is to be able to promote the clustering of inflammasome adaptors, which is essential for induced proximity-mediated activation of caspase-1 ( 3). Active NLRPs and ALRs trigger multiple innate immune effector pathways, but by far the best established function of these PYD-containing proteins is the assembly of inflammasomes, which are large multiprotein platforms that form in response to infection and tissue damage and are responsible for the activation of inflammatory caspases, in particular caspase-1 ( 1, 2). ![]() ![]() While Toll-like receptors (TLRs) utilize their TIR domain and RIG-I-like receptors (RLRs) and NLRCs their CARD for downstream signaling upon activation, NLRPs and AIM2-like receptors (ALRs) recruit signaling adaptors through their PYRIN domain (PYD). In response to pathogen infection, tissue damage or environmental stress, inflammatory mediators including cytokines, type I interferons (IFNs), and anti-microbial factors are produced. The innate immune system relies on germline-encoded pattern recognition receptors (PRRs) to detect threats against tissue homeostasis. In this review, we summarize the function of PYD-containing NLRPs and ALRs and address their contribution to innate immunity, host defense, and immune-linked diseases. In addition, they have been implicated in metabolic diseases. However, mutations in these PRRs have been linked to the development of auto-inflammatory and autoimmune diseases. NLRPs and ALRs both encode a PYD, which is crucial for relaying signals that result in an efficient innate immune response through activation of several key innate immune signaling pathways. In particular, Nod-like receptors containing a pyrin domain (PYD), called NLRPs, and AIM2-like receptors (ALRs) have been shown to play a critical role in host defense by facilitating clearance of pathogens and maintaining a healthy gut microflora. Lurie Comprehensive Cancer Center, Interdepartmental Immunobiology Center and Skin Disease Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USAĬytosolic pattern recognition receptors (PRRs) sense a wide range of endogenous danger-associated molecular patterns as well as exogenous pathogen-associated molecular patterns. 1Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.Andrea Dorfleutner 1 and Christian Stehlik 1,2* ![]()
0 Comments
Leave a Reply. |