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NLRs at the intersection of cell death and immunity

Nature Reviews Immunology volume 8, pages 372–379 (2008)Cite this article

Key Points

  • NLR (nucleotide-binding domain, leucine-rich repeat containing) family proteins structurally and functionally resemble APAF1 (apoptotic-protease activating factor 1), an apoptotic mediator, and the NBS-LRR (nucleotide-binding site, leucine-rich repeats) proteins, which help to mediate cell death in plants.

  • Pyronecrosis and pyroptosis are two pathways of cell death initiated in response to pathogens. Both feature degradation of the plasma membrane and the pro-inflammatory release of cellular contents. Pyroptosis is dependent on caspase-1, whereas pyronecrosis is not.

  • Several NLR proteins mediate caspase-1 pathway activation through their participation in NLR-specific inflammasomes. NLR and inflammasome activation is analogous to APAF1 and apoptosome formation.

  • NLRP1 inflammasome activity is regulated by the anti-apoptotic mitochondrial factors BCL-2 (B-cell lymphoma 2) and BCL-XL.

  • NAIP5 (neuronal apoptosis inhibitory protein 5) mediates cell death in response to Legionella pneumophila, and NLRP1 mediates cell death in response to anthrax lethal toxin. In both cases, cell death requires caspase-1, and is thereby thought to be pyroptosis.

  • Expression of disease-associated hyperactive mutants of NLRP3 induces pyronecrosis. This pathway is also activated in response to intracellular infection by Shigella flexneri.

Abstract

Inflammation is a crucial element of the host response to cellular insult. Pathogen-induced inflammation includes a molecular pathway which proceeds through activation of the protease caspase-1 to the release of the inflammatory cytokines interleukin-1 (IL-1) and IL-18. Importantly, pathogens may also induce forms of cell death that have inherently pro-inflammatory features. Here, we review recent evidence demonstrating that NLR (nucleotide-binding domain, leucine-rich repeat containing) family proteins serve as a common component of both caspase-1-activated apoptotic pathways and caspase-independent necrotic pathways. Parallels are drawn between NLR protein function and the activity of structurally similar proteins involved in cell death: the apoptotic mediator APAF1 (apoptotic-protease-activating factor 1) and the plant disease resistance NBS-LRR (nucleotide-binding site leucine-rich repeats) proteins.

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Figure 1: NLR proteins are structurally similar to the pro-apoptotic protein APAF1 and the plant cell-death mediating NBS-LRR proteins.
Figure 2: Comparison of APAF1 and NLRP3 cell-death pathways.
Figure 3: Specificity of the NLR proteins involved in the induction of cell death.

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Acknowledgements

J.P.-Y.T. is supported by NIH grants and the SPAR award. D.T.B. is supported by the Lineberger postdoctoral award.

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599-7295, North Carolina, USA

    Jenny P.-Y. Ting, Stephen B. Willingham & Daniel T. Bergstralh

  2. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, 27599-7295, North Carolina, USA

    Jenny P.-Y. Ting

  3. Curriculum in Genetics, University of North Carolina at Chapel Hill, Chapel Hill, 27599-7295, North Carolina, USA

    Jenny P.-Y. Ting & Stephen B. Willingham

  4. Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, 27599-7295, North Carolina, USA

    Daniel T. Bergstralh

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Correspondence to Jenny P.-Y. Ting.

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FURTHER INFORMATION

HUGO gene nomenclature, NLR family

Glossary

Membrane blebbing

Breakdown of the cytoskeleton during apoptosis results in 'blebbing' or bubbling of the plasma membrane. These blebs eventually separate from the cell to become apoptotic bodies, which are small membrane-enclosed packages of cytoplasm. Apoptotic bodies are ultimately engulfed by phagocytic cells and their contents are recycled.

Nuclear condensation

A hallmark of apoptosis is pyknosis, or the condensation of chromatin into compact spots along the nuclear membrane. During pyknosis, the nucleus itself may also shrink.

Cryopyrin-associated periodic syndrome

(CAPS). An autosomal dominant condition arising from mutations in NLRP3. CAPS has only recently been recognized as a single condition, and represents a range of disease severity that was formerly thought to be three distinct diseases: FCAS (familial cold autoinflammatory syndrome), Muckle-Wells syndrome and CINCA/NOMID (chronic infantile neurological cutaneous articular syndrome / neonatal onset multisystem inflammatory disease). Patients suffering from CAPS develop spontaneous inflammation and excessive release of the cytokine IL-1β, and may also suffer from arthralgia, deafness and hives.

Knockdown

This term is used to describe the decrease in mRNA or protein expression that results from RNA interference.

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Ting, JY., Willingham, S. & Bergstralh, D. NLRs at the intersection of cell death and immunity. Nat Rev Immunol 8, 372–379 (2008). https://doi.org/10.1038/nri2296

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