Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome

Cell Microbiol. 2010 Aug;12(8):1046-63. doi: 10.1111/j.1462-5822.2010.01450.x. Epub 2010 Feb 9.


Interleukin-1beta (IL-1beta) represents one of the most important mediators of inflammation and host responses to infection. Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, induces IL-1beta secretion at the site of infection, but the underlying mechanism(s) are poorly understood. In this work we show that Mtb infection of macrophages stimulates caspase-1 activity and promotes the secretion of IL-1beta. This stimulation requires live intracellular bacteria expressing a functional ESX-1 secretion system. ESAT-6, an ESX-1 substrate implicated in membrane damage, is both necessary and sufficient for caspase-1 activation and IL-1beta secretion. ESAT-6 promotes the access of other immunostimulatory agents such as AG85 into the macrophage cytosol, indicating that this protein may contribute to caspase-1 activation largely by perturbing host cell membranes. Using a high-throughput shRNA-based screen we found that numerous NOD-like receptors (NLRs) and CARD domain-containing proteins (CARDs) were important for IL-1beta secretion upon Mtb infection. Most importantly, NLRP3, ASC and caspase-1 form an infection-inducible inflammasome complex that is essential for IL-1beta secretion. In summary, we show that recognition of Mtb infection by the NLRP3 inflammasome requires the activity of the bacterial virulence factor ESAT-6, and the subsequent IL-1beta response is regulated by a number of NLR/CARD proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Bacterial / immunology
  • Antigens, Bacterial / metabolism*
  • Bacterial Proteins / immunology
  • Bacterial Proteins / metabolism*
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / immunology
  • Caspase 1 / biosynthesis
  • Cytoskeletal Proteins / biosynthesis*
  • Cytoskeletal Proteins / immunology
  • Host-Pathogen Interactions*
  • Humans
  • Interleukin-1beta / metabolism*
  • Macrophages / immunology
  • Macrophages / microbiology*
  • Mycobacterium tuberculosis / immunology*
  • Mycobacterium tuberculosis / pathogenicity
  • NLR Family, Pyrin Domain-Containing 3 Protein


  • Antigens, Bacterial
  • Bacterial Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • ESAT-6 protein, Mycobacterium tuberculosis
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • Caspase 1