Inhibiting the inflammasome: one domain at a time

Abstract

Summary Inflammasomes are protein complexes that promote the maturation and release of pro-inflammatory cytokines and danger signals as well as pyroptosis in response to infections and cellular stress. Inflammasomes consist of a sensor, an adapter, and the effector caspase-1, which interact through homotypic interactions of caspase recruitment domains (CARDs) or PYRIN domains (PYDs). Hence, decoy proteins encoding only a CARD or PYD, COPs and POPs, respectively, are assumed to inhibit inflammasome assembly. Sensors encoding a PYD belong to the families of NOD-like receptors containing a PYD (NLRPs) or AIM2-like receptors (ALRs), which interact with the PYD and CARD-containing adapter ASC through homotypic PYD interactions. Subsequently, ASC undergoes PYD-dependent oligomerization, which promotes CARD-mediated interactions between ASC and caspase-1, resulting in caspase-1 activation. POPs are suggested to interfere with the interaction between NLRPs/ALRs and ASC to prevent nucleation of ASC and therefore prevent an oligomeric platform for caspase-1 activation. Similarly, COPs are suggested to bind to the CARD of caspase-1 to prevent its recruitment to the oligomeric ASC platform and its activation. Alternatively, the adapter ASC may regulate inflammasome activity by expressing different isoforms, which are either capable or incapable of assembling an oligomeric ASC platform. The molecular mechanism of inflammasome assembly has only recently been elucidated, but the effects of most COPs and POPs on inflammasome assembly have not been investigated. Here we discuss our model of COP and POP-mediated inflammasome regulation.

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

“…Several proteins have been proposed to interfere with the assembly of inflammasomes. Decoy proteins encoding PYD or CARD only domains are believed to inhibit inflammasome assembly by interfering with PYD‐PYD or CARD‐CARD homotypic interactions and thereby blocking the recruitment of adaptor and effector proteins to the complex (Figure ). Similar to the repertoire of ALRs and NLRPs, PYD‐only regulators (POPs) and CARD‐only regulators (COPs) are poorly conserved in mammals.…”

“…Three COPs have been identified; these proteins are all encoded within the caspase‐1 locus in human and are absent from the mouse genome. They are all very homologous to the caspase‐1 CARD and are believed to be the result of recent duplication of the caspase‐1 gene . COPs all are predicted to function as caspase‐1 decoy proteins that blocks the recruitment of caspase‐1 to inflammasomes.…”

The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease

“…Within this protein complex, pro-caspase-1 is activated by induced proximity-mediated oligomerization (Martinon et al, 2002; Lu et al, 2014). The underlying assembly mechanism of this ternary complex has recently been delineated, and indicates that PRR activation triggers prion-like, self-perpetuating ASC polymerization into filaments, which is initialized by PRR induced ASC PYD nucleation (Cai et al, 2014; Lu et al, 2014; Franklin et al, 2014; Dorfleutner et al, 2015) . PRRs localize to the end of the hollow ASC filaments and allow efficient self-propagation of the ASC PYD , whereby the ASC CARD is flexible linked to the outside of the filaments, allowing recruitment and clustering of pro-caspase-1 (Lu et al, 2014).…”

The inflammasome: firing up innate immunity

“…The review by Dorfleutner et al . features information on the biological activities of POPs, COPs, and vPOPs in the inhibition or engagement of inflammasome functions and NF‐κB signaling. The authors provide an in‐depth look at the biochemistry and structural elements of POPs and COPs that gives insight into the complexity of the mammalian immune system.…”