Critical role for NLRP3 in necrotic death triggered by Mycobacterium tuberculosis
Open accessAbstract
Induction of necrotic death in macrophages is a primary virulence determinant of Mycobacterium tuberculosis. The ESX-1 secretion system and its substrate ESAT-6 are required for M. tuberculosis to induce necrosis, but host factors that mediate the ESAT-6-promoted necrosis remain unknown. Here we report that ESAT-6-promoted necrotic death in THP-1 human macrophages is dependent on the NLRP3 inflammasome, as shown by RNA interference and pharmacological inhibitions. Phagosomes containing ESAT-6-expressing M. tuberculosis recruit markers previously associated with damaged phagosomal membrane, such as galectin-3 and ubiquitinated protein aggregates. In addition, ESAT-6 promoted lysosomal permeabilization by M. tuberculosis. ESAT-6 mutants defective for ubiquitination were unable to trigger NLRP3 activation and necrotic death. Furthermore, Syk tyrosine kinase, recently implicated in NLRP3 activation during fungal and malarial infections, was necessary for mediating the ESAT-6-promoted necrosis and NLRP3 activation. Our results thus link phagosomal damage and Syk activity to NLRP3-mediated necrotic death triggered by M. tuberculosis ESAT-6 during infection.
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This phagosome-to-cytosol transition process has consequences for the host cell, such as induction of the cGAS/STING/TBK1/IRF-3/type I interferon signalling axis and NLRP3 inflammasome activation.
“an important cell biological process that has numerous consequences for the host cell, such as induc-tion of the cGAS/STING/TBK1/IRF-3/type I interferon signalling axis and NLRP3 inflammasome activation (69)(70)(71)(72)(73)(74)(75).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [69]
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- Authors
- Wong, K., & Jacobs Jr, W. R.
- Affiliations
- Albert Einstein College of Medicine (US)
- ORCID
- Wong, Ka‐Wing
- Venue
- Cellular Microbiology
- Publisher
- Wiley
- Published
- 2011-07-11
- Volume
- 13
- Issue
- 9
- Pages
- 1371-1384
- ISSN
- 1462-5814 (ISSN-L)
- 1462-5822
- PMC
- PMC3257557
- OpenAlex
- W1552410459
- Cited by
- 209
- References
- 48
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 15 · 2023: 7 · 2022: 14 · 2021: 12 · 2020: 17 · 2019: 12 · 2018: 12 · 2017: 16 · 2016: 12 · 2015: 21 · 2014: 15 · 2013: 22 · 2012: 11
- FWCI
- 10.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cellular Microbiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AI0-51519, AI26170)
- Center for AIDS Research, University of Washington
- National Institute of Allergy and Infectious Diseases (R01AI026170, AI-26170, R37AI026170)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- NLRP3 inflammasome, necrosis, Mycobacterium tuberculosis, ESAT-6, ESX-1 secretion system, macrophages, lysosomal membrane permeabilization, ubiquitination, Syk, galectin-3, THP-1 cells, host-pathogen interaction
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Antigens, Bacterial, Bacterial Proteins, Carrier Proteins, Cell Line, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Genetic Complementation Test, Humans, Macrophages, Mycobacterium tuberculosis, Necrosis, Phagocytosis, Phagosomes, RNA Interference
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