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Interleukin-1β (IL-1β) Processing Pathway

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Sci. Signal.  19 Jan 2010:
Vol. 3, Issue 105, pp. cm2
DOI: 10.1126/scisignal.3105cm2

Abstract

The innate immune system senses molecular patterns from invading microorganisms. Once activated, it orchestrates the inflammatory response by secreting proinflammatory cytokines, such as interleukin-1 (IL-1)–type cytokines, in particular IL-1β. IL-1 mediates the expression of a vast array of genes involved in secondary inflammation. IL-1–responsive genes coordinate all aspects of local inflammation and also attract and activate cells of the adaptive immune system at sites of infection. Moreover, the innate immune system can also sense a wide range of nonmicrobial molecular patterns that represent danger or damage signals. These signals activate the NALP3-inflammasome pathway, which plays a central role in acute and chronic sterile inflammation. Here, we describe the essential components of the NALP3-inflammasome that control processing and release of IL-1β.

Description

Stimuli that activate the NALP3 inflammasome

NALP [NACHT-, leucine-rich repeat (LRR)– and PYD-containing protein] 3 belongs to the large family of intracellular NOD-like receptors (NLRs) that sense pathogen-associated molecular patterns (PAMPs), such as viral DNAs, bacterial peptidoglycans, and toxins (1, 2). NALP3 also senses nonmicrobial danger or damage signals (DAMPs), such as monosodium urate crystals (MSU) or calcium pyrophosphate dihydrate (3), low potassium (4), ATP (5), amyloid-β (6), reactive oxygen species (ROS) (7), DNA (8), heat shock proteins (HSP90) (9), aluminum salts (10), asbestos and silica crystals (7, 11, 12), skin irritants (13), and ultraviolet (UV) irradiation (14).

The central role of NALP3 in processing and release of IL-1β

The relation of NALP3 to the IL-1 pathway was based on the discovery of inflammasomes. The first inflammasome, the NALP1 inflammasome, was identified in 2002 by the Tschopp lab as a high-molecular-weight complex that participated in the activation of the inflammatory proteases caspase-1 and -5 and in subsequent maturation of interleukin-1β (IL-1β) (15). Through analysis of a gain-of-function mutation in the related gene encoding NALP3 that produced an amino acid substitution of Arg260 to Trp (R260W), NALP3 was subsequently identified as the cause of increased inflammasome activity and enhanced IL-1β release associated with Muckle-Wells disease, a rare febrile human disease (16, 17). Alternative names for the NALP3 gene or the encoded protein are cold-induced autoinflammatory syndrome 1 (CIAS1), cryopyrin, and pyrin-containing Apaf-1–like (PYPAF1).

Structure of NALP3-inflammasome components

The core structure of the NALP3 inflammasome is formed by three proteins: NALP3, the adaptor protein ASC [apoptosis-associated specklike protein containing a caspase recruitment domain (CARD)], and caspase-1. Caspase-1 was initially discovered as an interleukin-1β–converting enzyme (ICE) (18, 19). Mice deficient in this enzyme are defective in production of mature IL-1β and are resistant to endotoxic shock (20, 21).

Like other NLRs, NALP3 is a multidomain protein containing a C-terminal LRR region, a central nucleotide domain called the NACHT domain [domain present in neuronal apoptosis inhibitory protein (NAIP), the major histocompatibility complex (MHC) class II transactivator (CIITA), HET-E, and TP1], a NAD (NACHT-associated) domain, and a PYRIN (PYR) domain, which is the N-terminal effector domain (2, 22).

These domains fulfill specific tasks. The LRR is involved in ligand sensing of PAMPs and DAMPs and in autoregulation (2). The NACHT domain is involved in oligomerization to form a high-molecular-weight active inflammasome. With the NACHT domain, NALP3 binds ATP and dATP, which is released from damaged cells (5). Nucleotide binding is necessary for oligomerization of the NACHT domain (23).

CARD and PYR domains are “death-fold” domains that facilitate dimerization or trimerization by homotypic interactions with corresponding CARD or PYR domains in other proteins (2).

The C-terminal PYD domain of NALP3 interacts with and recruits the adaptor ASC through PYD-PYD interactions. ASC contains an N-terminal PYD and a C-terminal CARD and is required for inflammasome formation. Caspase-1 contains a CARD domain followed by a domain containing the catalytic cysteine residue. The CARD domain within ASC binds the CARD domain of caspase-1 and thereby recruits caspase-1 to the inflammasome (5, 15).

Formation of the inflammasome through interactions mediated by the death-fold domains promotes dimerization or oligomerization of caspase-1, which leads to the formation of an active enzyme that cleaves the cytosolic 33-kD pro-IL-1β precursor at the site Tyr-Val-His-Asp (16) /Ala (17). Cleavage results in the 17-kD mature IL-1 protein (18, 19, 24, 25).

Efficient secretion of mature IL-1β requires not only processing of the IL-1β precursor by active caspase-1 but also regulation of its release (Fig. 1). Extracellular ATP promotes the secretion of mature IL-1β and thus provides an additional signal for efficient secretion of IL-1β. ATP acts through the nucleotide receptor P2X7. Absence of P2X7 receptors impairs IL-1β secretion (5, 26-30).

Fig. 1

Pathway image captured from the dynamic graphical display of the information in the Database of Cell Signaling on 21 December 2009. For a key to the colors and symbols and to access the underlying data, please visit the pathway (About Connections Map).

Relevance of the NALP3-inflamamsome pathway for human disease

Studies in mice deficient in NALP3, ASC, or caspase-1 confirm its crucial role in processing of pro-IL-1β (3, 5, 13, 31-33). Mutations in NALP3 are found in a number of inflammatory human diseases that are characterized by increased systemic levels of IL-1β (2, 16, 17, 34). These syndromes and also more common inflammatory conditions, such as gout or type II diabetes, can be treated successfully with recombinant IL-1 receptor antagonist (IL-1RA, commercially known as Anakinra) (35, 36) or the IL-1 Trap (Rilonacept) (37, 38), proving that IL-1 and the inflammasomes are at the apex of complex inflammatory syndromes.

Pathway Details

Scope: Canonical

Pathway URL: About Connections Map

References

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