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Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
06:52

Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages

Published on: May 21, 2018

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Mycobacterial EST12 activates a RACK1-NLRP3-gasdermin D pyroptosis-IL-1β immune pathway

Zilu Qu1, Jin Zhou2, Yidan Zhou3

  • 1Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology of School of Basic Medical Sciences and Department of Allergy of Zhongnan Hospital, Wuhan University, Wuhan 430071, China.

Science Advances
|October 24, 2020
PubMed

Insights

Mycobacterium tuberculosis secretes EST12, a protein that triggers pyroptosis by targeting RACK1 and NLRP3. This immune response is crucial for controlling tuberculosis infection.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Pyroptosis is a key inflammatory cell death pathway for combating infections.
  • The role of macrophage pyroptosis-related proteins in Mycobacterium tuberculosis (M.tb) infection remains largely unknown.

Purpose of the Study:

  • To identify and characterize M.tb secreted proteins that induce pyroptosis in macrophages.
  • To elucidate the molecular mechanism by which M.tb triggers pyroptosis and its role in host immunity.

Main Methods:

  • Identification of a novel M.tb secreted protein, EST12 (Rv1579c).
  • Investigation of EST12 interaction with host receptor RACK1 and its effect on NLRP3 inflammasome activation.
  • Structural analysis of EST12-RACK1 binding.
  • Assessment of M.tb EST12-deficient strain's virulence in vitro and in vivo.

Main Results:

  • EST12 directly binds to macrophage RACK1, recruiting UCHL5 to deubiquitinate NLRP3.
  • This interaction leads to NLRP3 inflammasome activation, triggering pyroptosis (caspase-1/11, gasdermin D, IL-1β).
  • The Y80 amino acid in EST12 is critical for RACK1 binding.
  • An EST12-deficient M.tb strain showed increased susceptibility to infection.

Conclusions:

  • EST12 is a novel M.tb virulence factor that induces pyroptosis via the RACK1-NLRP3 inflammasome pathway.
  • RACK1 functions as an endogenous host sensor for M.tb infection.
  • EST12-induced pyroptosis is essential for controlling M.tb infection and mounting an effective immune response.

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