The discovery of evolutionarily conserved large gene families has been pivotal in the discovery of new innate immune pathways. This is exemplified by the Toll protein in Drosophila melanogaster and its mammalian para- logues, the Toll-like receptors (TLRs) 1–3 . The transmem- brane Toll molecule was initially identified as important for the specification of dorsal–ventral development in flies 4 . Subsequent analyses showed decreased survival of genetic mutants of Toll after infection with the fungus Aspergillus fumigatus or with Gram-positive bacteria 5 . Toll recruits a complex of adaptors (including myeloid differentiation primary-response gene 88, MyD88, and TUBE) and a serine-threonine kinase (denoted Pelle) leading to the activation of the dorsal and dorsal-related immunity factor (DIF) pathways. In 1997, the first mammalian TLR was discovered 6 . It was predicted to contain a transmembrane region with an extracellular leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to that of the human interleukin-1 (IL-1) receptor, which is now known as the Toll IL-1R (TIR) domain. Similar to D. melanogaster Toll, mammalian TLRs signal through adaptors (including MyD88; TIRAP (TIR domain-containing adaptor protein, also known as MAL); TRIF (TIR- domain-containing adaptor inducing interferon-β also known as TICAM ) and TRAM (TRIF-related adaptor molecule), and serine-threonine kinases, leading to nuclear factor-κB (NF-κB) activation, cytokine produc- tion and changes in membrane-receptor expression. A seminal genetic approach that relies on endotoxin resistance in C3H/HeJ mice showed that the resistance allele corresponds to a missense mutation in the gene encoding TLR4 (REF. 7). This demonstrates that TLR4 is required for mice to mount an efficient response to the endotoxin lipopolysaccharide (LPS), therefore open- ing the floodgate of discoveries that have shown that TLRs are sensors of microbial products. So far, there are 13 mammalian TLRs that recognize a wide range of microbial products. The TLR field provides examples of immune genes that are similar in higher vertebrates and invertebrates. In early 2000, we and other groups independently described the existence of a novel gene family — found in both plants and mammals — that might also regulate immune responses 8,9 . Later, we described the entire family in detail and named it the CATERPILLER (CARD (caspase-recruitment domain) transcription enhancer, R (purine)-binding, pyrin, lots of leucine repeats) gene family 10,11 . This family was identified by the scanning of genes with a similar structure to the MHC class II transactivator (MHC2TA) gene 10,11 . MHC2TA encodes MHC class II transactivator (CIITA), which is a protein with a nucleotide-binding domain (NBD), followed by LRRs 12 . Therefore, by definition, all CATERPILLER proteins contain these two domains. The Inohara-Nunez group described a similar family that they called the nucleotide-binding oligomerization domain (NOD)-leuine-rich repeat (LRR) family (the NOD-LRR family) 13,14 . A more recent review suggested the name NACHT (domain present in NAIP, CIITA, HET-E and TP1)-leucine-rich repeat (LRR) family (the NACHT-LRR family) 15,16 . CATERPILLERs include several subgroups that can be distinguished by their amino (N)-terminal domains: *Department of Microbiology-Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599, USA. ‡ Genetics and Genomics Branch NIAMS, National Institutes of Health, Bethesda, Maryland 20892, USA. § Division of Rheumatology, Allergy, and Immunology and Department of Pediatrics, University of California at San Diego, La Jolla, California 92093-0635, USA. Correspondence to J.P.-Y.T. e-mail: panyun@med.unc.edu doi:10.1038/nri1788 Paralogues Homologous sequences found within a single species. Dorsal Rel/nuclear factor-κB transcription factor family member found in Drosophila melanogaster. Dorsal-related immunity factor (DIF). A Drosophila melanogaster transcription factor that is a Rel-homologue, and is important for dorsal– ventral axis determination. CATERPILLERs, pyrin and hereditary immunological disorders Jenny P.-Y. Ting*, Daniel L. Kastner ‡ and Hal M. Hoffman § Abstract | The newly described CATERPILLER family (also known as NOD-LRR or NACHT- LRR) is comprised of proteins with a nucleotide-binding domain and a leucine-rich region. This family has gained rapid prominence because of its demonstrated and anticipated roles in immunity, cell death and growth, and diseases. CATERPILLER proteins are structurally similar to a subgroup of plant-disease-resistance (R) proteins and to the apoptotic protease activating factor 1 (APAF1). They provide positive and negative signals for the control of immune and inflammatory responses, and might represent intracellular sensors of pathogen products. Most importantly, they are genetically linked to several human immunological disorders. REVIEWS NATURE REVIEWS | IMMUNOLOGY VOLUME 6 | MARCH 2006 | 183