Pyrin domain

Proteins containing PYDs function as cytosolic pattern recognition receptors (PRRs) that sense damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs).^[5] Homotypic interactions between PYDs in receptor and adaptor proteins trigger the downstream formation of the inflammasome.^[4]

First, receptor proteins (such as NLRs and ALRs) are activated by their putative DAMP or PAMP ligands. These receptors undergo a conformational change, exposing their PYD.^[8] Generally, an adaptor protein (ASC) containing both a PYD and a caspase recruitment domain (CARD) is recruited, forming a PYD-PYD electrostatic interaction with the receptor's domain. More ASC-PYDs spontaneously self-oligomerize and form a multi-protein complex called an inflammasome. Pro-caspase-1 and caspase-8 are activated through an induced proximity mechanism. Caspase activity regulates multiple downstream pathways to trigger pyroptosis and the secretion of pro-inflammatory cytokines.^[4][8]

Types of proteins containing a PYD include adaptors, apoptosis-associated speck-like protein containing a CARD (ASC), regulatory proteins such as pyrin or pyrin-only proteins (POPs), receptors like NOD-like receptors containing a pyrin domain (NLRPs), and AIM2-like receptors (ALRs).^[5][8]

ASC is an adaptor protein that is part of apoptosis, pro-caspase 1 recruitment and activation, as well as NF-κB transcription factor activation. ASC contains only two domains: the PYD at the N-terminus and a CARD at the C-terminus. PYD interactions between ASC lead to oligomerization, forming puncta or "specks" that become visible microscopically.^[7][9] The CARD recruits pro-caspase-1, which undergoes proximity-induced autocleavage to form the active caspase-1, which in turn triggers maturation of IL-1β and IL-18.^[10]

NOD-like receptors exist in an inactive form until their ligand induces a conformational change. Some NLRs, such as NLRP1 and NLRP2, have a straightforward mechanism by which the receptor binds to a PAMP, triggering its activation, oligomerization and PYD-PYD ASC recruitment.^[7][8] In contrast, NLRP3 (also known as cryopyrin) is the most well-studied NLR with a pyrin domain and has several diverse agonists. Proposed methods of its activation are more nuanced, involving intermediate effectors rather than a direct ligand-receptor interaction. An efflux of ATP due to tissue damage leading to an increase in Ca²⁺, mitochondrial reactive oxygen species production due to cellular stress and lysosomal rupture releasing excess H⁺ have all been proposed to inhibit different cofactors that normally inactivate NLRP3.^[8]

Absent in melanoma 2-like (AIM2-like) receptors function as recognition of foreign double-stranded DNA. Two ALRs with pyrin domains, AIM2 and IFI16, assemble inflammasomes; AIM2 in the cytosol and IFI16 moves between the nucleus and cytosol, functioning as a nuclear pathogen sensor.^[11] Unlike NLRPs, which function in cytosolic PAMP and DAMP recognition, ALRs mainly act within the nucleus, oligomerizing along the DNA staircase.^[8]

Pyrin-only proteins are unlike other PYD-containing proteins which contain a PYD with one or more other domains. Different POPs have electrostatic and structural similarities to the specific PYD they regulate.^[5] Most are encoded near the same genes as the pyrin-containing proteins they inhibit; POP1 and POP2 are postulated to have arisen by exon duplication.^[7] Since most inflammasomes are formed by aggregation due to PYD-PYD interactions, POPs instead bind to PYDs preventing polymerization and therefore regulating and/or resolving inflammation response.^[5]