CATERPILLER: A Novel Gene Family Important in Immunity, Cell Death, and Diseases

Abstract

The newly discovered CATERPILLER (CLR) gene family encodes proteins with a variable but limited number of N-terminal domains, followed by a nucleotide-binding domain (NBD) and leucine-rich repeats (LRR). The N-terminal domain consists of transactivation, CARD, Pyrin, or BIR domains, with a minority containing undefined domains. These proteins are remarkably similar in structure to the TIR-NBD-LRR and CC-NBD-LRR disease resistance (R) proteins that mediate immune responses in plants. The NBD-LRR architecture is conserved in plants and vertebrates, but only remnants are found in worms and flies. The CLRs regulate inflammatory and apoptotic responses, and some act as sensors that detect pathogen products. Several CLR genes have been genetically linked to susceptibility to immunologic disorders. We describe prominent family members, including CIITA, CARD4/NOD1, NOD2/CARD15, CIAS1, CARD7/NALP1, and NAIP, in more detail. We also discuss implied roles of these proteins in diversifying immune detection and in providing a check-and-balance during inflammation.

Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization

“…The majority of NLR proteins contain an N-terminal PYD followed by a NOD/NACHT domain and a regulatory C-terminal LRR domain, which is believed to function as a ligand-binding domain. 5,26,36 Many NLR proteins interact with ASC via PYD-PYD interactions, but their specific ligands and their exact role in inflammation is largely unknown. 5,26 One way to gain insights into the function of the individual NLRs is to reconstitute the NLR complexes in a cell line, such as 293T, that is deficient in ASC, procaspase-1 and proinflammatory NLRs.…”

“…5,26,36 Many NLR proteins interact with ASC via PYD-PYD interactions, but their specific ligands and their exact role in inflammation is largely unknown. 5,26 One way to gain insights into the function of the individual NLRs is to reconstitute the NLR complexes in a cell line, such as 293T, that is deficient in ASC, procaspase-1 and proinflammatory NLRs. Here we have described a 293T cell-based reconstitution system that allows the determination of the pro-or antiinflammatory potential of molecules that interact with ASC and procaspase-1.…”

“…Cryopyrin belongs to the NACHT-LRR (NLR) protein family, which includes NOD1, NOD2, Ipaf and 14 other family members known as NALPs. 26,5 All family members contain a central nucleotide-binding oligomerization domain (NOD)/domain present in NAIP, CIITA, HET-E and TP1 (NACHT), and a C-terminal leucine-rich repeat (LRR) domain. The disease-associated cryopyrin mutations are located within or near the NOD/NACHT domain, 27 suggesting that these mutations might affect oligomerization of cryopyrin.…”

Reconstructing immune phylogeny: new perspectives

“…The postulated role of the VLRs as alternative mediators of adaptive immunity might have an even more ancient history within the broader functional roles of other metazoan LRRcontaining proteins, which include the Toll-like receptor (TLR) 94 , CATERPILLER (caspase-recruitment domain, transcription enhancer, R (purine)-binding, pyrin, lots of LRRs) 100 and Slit-homologue protein families 101,102 . The TLRs have particularly broad distributions in phylogeny and are closely involved in mammalian immune surveillance [103][104][105] .…”

“…Pattern recognition by TLRs does not rely on somatic change; however, there is increasing evidence for functionally advantageous polymorphisms that, for example, improve resistance to bacterial infection 108 , as well as increasing evidence for combinatorial pairing 109 . Intracellular LRRcontaining proteins that mediate recognition of intracellular infection, modulate signalling and regulate apoptosis have also been described 100,110 . Our preliminary phylogenetic analysis of lamprey and hagfish VLRs indicates that a single LRR protein might have been recruited from a pre-existing family; this protein subsequently would have undergone rapid evolution and divergence (to function as an immune mediator).…”