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CATERPILLERs, pyrin and hereditary immunological disorders

Nature Reviews Immunology volume 6, pages 183–195 (2006)Cite this article

Key Points

  • CATERPILLER proteins contain the nucleotide-binding-domain-leucine-rich-repeat (NBD-LRR) motif, and they are similar to disease resistance genes (R) found in plants that mediate immune defence to microbial pathogens.

  • MHC class II transactivator (CIITA) is a master transcriptional regulator of MHC class II genes that activates MHC class II promoters by promoting the loading of DNA-binding proteins and histone-modifying enzymes.

  • Mutations in cold induced autoinflammatory syndrome (CIAS1) are associated with a continuum of autoinflammatory diseases including familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and neonatal-onset multisystem disease.

  • Cryopyrin has a key role in innate immunity by regulating cytokine responses at a transcriptional and post-translational level.

  • Interleukin-1 (IL-1) is a central mediator of CIAS1-associated disorders, as was shown by the remarkable clinical responses to IL1-targeted therapy.

  • Mediterranean fever is the locus that is mutated in familial Mediterranean fever, which is a recessively inherited systemic autoinflammatory disease with unprovoked episodes of fever, abdominal or chest pain, arthritis, or rash.

  • The amino-terminal 92 amino acids of pyrin is the prototype for the motif that bears its name, and represents the region that interacts with ASC (apoptosis-associated speck-like protein containing a CARD) to mediate IL-1β processing, nuclear-factor-κB activation, and apoptosis.

  • Both pro- and anti-inflammatory roles have been demonstrated for pyrin.

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.

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Figure 1: Domain organization of the CATERPILLER proteins.
Figure 2: Mechanism of action of CIITA.
Figure 3: Mechanism of action of cryopyrin.
Figure 4: Proposed mechanisms of pyrin action.

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Acknowledgements

We would like to thank B. Davis for his helpful discussions, and acknowledge the support of National Institutes of Health.

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Authors and Affiliations

  1. Department of Microbiology-Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599, North Carolina, USA

    Jenny P.-Y. Ting

  2. Genetics and Genomics Branch NIAMS, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Daniel L. Kastner

  3. Division of Rheumatology, and Immunology and Department of Pediatrics, Allergy, University of California at San Diego, La Jolla, 92093-0635, California, USA

    Hal M. Hoffman

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  1. Jenny P.-Y. Ting
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Correspondence to Jenny P.-Y. Ting.

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DATABASES

OMIM

BLS

CIAS1

FCAS

FMF

MWS

NOMID

FURTHER INFORMATION

Infevers database

Glossary

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.

MHC class II transactivator

(CIITA). The master transcriptional regulator of MHC class II genes.

Penetrance

The frequency with which a genotype manifests itself in a given phenotype.

Single nucleotide polymorphisms

(SNP). Common DNA sequence polymorphisms among individuals.

Complementation group

Two genetic mutations that, when present in the same cell or organism, cause the appearance of wild-type traits.

Quantitative trait locus

A region of DNA associated with a specific trait that varies in a quantitative fashion, rather than dichotomously.

Histone-modifying enzymes

Enzymes such as acetylases and methylases that cause the covalent modification of histone tails.

Positional cloning

The process of identifying a gene based on its chromosomal position, including genetic and physical mapping.

Expressed sequence tags

A short partial cDNA sequence that represents a part of an expressed gene and can be mapped to a chromosomal position.

Founder effect

High frequency of a particular allele in a population because the population is derived from a small number of founders, one or more of whom carried that allele.

B30.2 domain

A 170 amino-acid globular domain found at the C-terminus of several proteins, first identified as the product of an isolated exon of the same name encoded in the MHC.

Intragenic convergence of haplotypes

The identification of a shared set of DNA markers within a gene among unrelated individuals with a specific disease, suggesting a common ancestral origin of the disease-associated chromosomes.

Behçet's disease

A disorder common in the Middle and Far East, characterized by oral and genital ulcerations, ocular inflammation, skin lesions, and a number of other inflammatory manifestations.

dN/dS ratio

The ratio of nonsynonymous to synonymous substitutions, which varies directly with the probability of evolutionary selection at a given locus.

14.3.3 protein family

A family of proteins involved in the regulation of intracellular signaling, cell-cycle control, and apoptosis.

Hypomorphic

A protein variant with reduced function.

TRIM5α

A tripartite motif (TRIM) cytoplasmic protein with a carboxy-terminal B30.2 domain that was recently shown to mediate innate intracellular resistance to retroviruses.

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Ting, JY., Kastner, D. & Hoffman, H. CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 6, 183–195 (2006). https://doi.org/10.1038/nri1788

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