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NALPs: a novel protein family involved in inflammation

Nature Reviews Molecular Cell Biology volume 4, pages 95–104 (2003)Cite this article

Key Points

  • On infection, microorganisms are efficiently recognized by Toll-like receptors (TLRs), which recognize invariant molecular structures called pathogen-associated molecular patterns (PAMPs) that are shared by many pathogens but are not expressed by their hosts.

  • Recognition of PAMPs by TLRs results in the activation of different intracellular signalling cascades, which, in turn, lead to the expression of various effector molecules. One of these, interleukin-1β (IL-1β), is defined as an 'alarm cytokine'; it is secreted by macrophages and initiates inflammation.

  • For IL-1β to be active, pro-IL-1β must first be processed to an active molecule and then secreted. The IL-1β-converting enzyme (ICE) — also known as caspase-1 — is responsible for this processing.

  • A novel family of cytoplasmic proteins containing NACHT, leucine-rich domains and either a Pyrin or CARD domain are involved in caspase-1 activation and therefore IL-1β cleavage.

  • One member of this family, designated NALP1, assembles into a complex with ASC, caspase-1 and caspase-5, forming the 'inflammasome'.

  • The NALP3 gene is mutated in three related autosomal-dominant autoinflammatory disorders, Muckle–Wells syndrome, familial cold urticaria, and in chronic infantile neurologic cutaneous and articular syndrome.

Abstract

A newly discovered family of cytoplasmic proteins — the NALPs — has been implicated in the activation of caspase-1 by the Toll-like receptors (TLRs) during the cell's response to microbial infection. Like the structurally related apoptotic protease-activating factor-1 (APAF-1), which is responsible for the activation of caspase-9, the NALP1 protein forms a large, signal-induced multiprotein complex, the inflammasome, resulting in the activation of pro-inflammatory caspases.

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Figure 1: Recognition of pathogen-associated molecular patterns by Toll-like receptors.
Figure 2: Domain structures of NALPs and subfamilies of the CATERPILLER protein family.
Figure 3: The inflammasome.
Figure 4: Model of lipopolysaccharide-induced activation and secretion of pro-inflammatory caspases and interleukin-1β.
Figure 5: Hypothetical mechanism of NALP3 activation.
Figure 6: Diseases associated with mutations in NALP3.

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Authors and Affiliations

  1. Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, Epalinges, CH-1066, Switzerland

    Jürg Tschopp, Fabio Martinon & Kimberly Burns

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  1. Jürg Tschopp
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Supplementary information

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DATABASES

LocusLink

APAF-1

ASC

CARD12

caspase-1

caspase-9

CIITA

IL-1β

IL-6

iNOS

Mater

MYD88

NALP1

NALP3

NOD1

NOD2

TIRAP

TLR-4

TLR-5

OMIM

Beckwith–Wiedemann syndrome

CINCA

familial cold autoinflammatory syndrome

familial Mediterranean fever

Muckle–Wells syndrome

CancerNet

breast cancer

FURTHER INFORMATION

Jürg Tschopp's laboratory

Pyrin domain

Glossary

PHAGOCYTIC LEUKOCYTES

If a microorganism begins to replicate in a host, it is usually recognized by the mononuclear phagocytes, or macrophages, that reside in tissues. The other main family of phagocytes are the neutrophils. Both types of phagocytic cell have a key role in innate immunity.

LIPOPOLYSACCHARIDE

(LPS). An important component of the outer membrane of Gram-negative bacteria (also known as endotoxin). This complex molecule consists of a lipid A anchor, a polysaccharide core and chains of carbohydrates.

LIPOTEICHOIC ACID

A polyol phosphate polymer bearing a strong negative charge. It is covalently linked to the peptidoglycan in some Gram-positive bacteria. It is strongly antigenic, but is generally absent in Gram-negative bacteria.

UNMETHYLATED CPG DNA

Bacterial DNA containing unmethylated CpG dinucleotide motifs.

LIPOARABINOMANNAN

(LAM). A wall component of mycobacteria. Purified LAM from virulent and attenuated strains of mycobacteria differ structurally, and these differences could contribute to their varying abilities to stimulate cytokine production in mononuclear cell cultures.

PYROGEN

A substance that causes the elevation of body temperature. Examples are cytokines produced by macrophages such as tumour-necrosis factor-α, interleukin (IL)-1 and IL-6.

BIR

A domain found in inhibitor of apoptosis proteins (IAP) and other proteins. Acts as a direct inhibitor of caspases.

GENOMIC IMPRINTING

The ability to mark a gene as coming either from the father or the mother. These differences involve methylation. Imprinting adds additional information to the inherited genome that might regulate spatial and temporal gene activity.

ORTHOLOGUES

Two genes related by speciation events alone, which typically have the same function.

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Tschopp, J., Martinon, F. & Burns, K. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 4, 95–104 (2003). https://doi.org/10.1038/nrm1019

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