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Cited by 190Inflammasome and immune disordersImmune Response and InflammationCalcium signaling and nucleotide metabolism

The NLRP3–inflammasome as a sensor of organelle dysfunction

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Seoane, Paula I., Lee, Bali, Hoyle, Christopher, Yu, Shi, Lopez-Castejon, Gloria, Lowe, Martin, Brough, David·2020·Journal of Cell Biology
DOI 10.1083/jcb.202006194PMC PMC7543090
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Abstract

Diverse pathogen- and damage-associated stresses drive inflammation via activation of the multimolecular NLRP3–inflammasome complex. How the effects of diverse stimuli are integrated by the cell to regulate NLRP3 has been the subject of intense research, and yet an accepted unifying hypothesis for the control of NLRP3 remains elusive. Here, we review the literature on the effects of NLRP3-activating stimuli on subcellular organelles and conclude that a shared feature of NLRP3-activating stresses is an organelle dysfunction. In particular, we propose that the endosome may be more important than previously recognized as a signal-integrating hub for NLRP3 activation in response to many stimuli and may also link to the dysfunction of other organelles. In addition, NLRP3–inflammasome-activating stimuli trigger diverse posttranslational modifications of NLRP3 that are important in controlling its activation. Future research should focus on how organelles respond to specific NLRP3-activating stimuli, and how this relates to posttranslational modifications, to delineate the organellar control of NLRP3.

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Crossref · 10.1083/jcb.202006194

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  • Recent studies show that dysfunction of organelles, such as lysosomes and mitochondria, can activate the NLRP3 inflammasome in the absence of external stimuli.

    “However, recent studies show that dysfunction of organelles, such as lysosomes and mitochondria, can activate the NLRP3 inflammasome in the absence of external stimuli15.”

    From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [15]

    The Lysosomes and NLRP3 and Mitochondria and NLRP3 sections link dysfunction of those organelles to inflammasome activation. But the Organelle involvement section describes that dysfunction as occurring in response to NLRP3-activating stimuli; the cited passages do not establish activation in the absence of external stimuli. Page numbers are not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Lysosomal dysfunction may trigger inflammasome activation in some systems.

    “in some systems, lysosomal dysfunction may trigger inflammasome activation15”

    From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [15]

  • The NLRP3 inflammasome is activated in INPP5D HET microglia and in microglia following acute inhibition of SHIP1.

    “We previously reported that the NLRP3 inflammasome is activated in INPP5D HET microglia and in microglia following acute inhibition of SHIP111,15.”

    From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [15]

    The cited paper discusses NLRP3 activation in other settings, including mitochondrial signaling (Mitochondria and NLRP3; page unavailable) and phosphatase regulation (Posttranslational modifications of NLRP3; page unavailable). Searches for INPP5D, SHIP1, and acute SHIP1 inhibition found no passage addressing NLRP3 activation in the specified microglia. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Seoane, P. I., Lee, B., Hoyle, C., Yu, S., Lopez-Castejon, G., Lowe, M., & Brough, D.
Affiliations
  • Manchester Academic Health Science Centre (GB)
  • Division of Infection, Immunity, and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK 2
Corresponding author
Brough, David
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2020-10-06
Volume
219
Issue
12
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.202006194
PMC
PMC7543090
OpenAlex
W3092041441
Cited by
190
References
11
Citations by year
2026: 28 · 2025: 45 · 2024: 47 · 2023: 29 · 2022: 34 · 2021: 6 · 2020: 1
FWCI
1.68
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Medical Research Council (MR/T016515/1)
  • Royal Society (104192/Z/14/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
NLRP3 inflammasome, organelle dysfunction, endosomes, signal integration, post-translational modification, inflammasome activation, inflammation
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Humans, Protein Processing, Post-Translational, Stress, Physiological, Organelles, Signal Transduction, Inflammasomes

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