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Author Spotlight: THP-1 Macrophage Response to LPS/ATP — Unveiling the Pyroptosis, Apoptosis, and Necroptosis Spectrum
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A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin

Qiyao Chai1, Shanshan Yu2, Yanzhao Zhong1,3

  • 1CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.

Science (New York, N.Y.)
|October 13, 2022
PubMed

Insights

Mycobacterium tuberculosis uses PtpB to inhibit the host inflammasome-pyroptosis pathway by dephosphorylating cell membranes, thus evading immune responses. Disrupting PtpB’s activity boosts immunity and reduces pathogen survival.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • The inflammasome pathway, involving gasdermin D (GSDMD) cleavage, triggers pyroptosis and cytokine release to combat infections.
  • Pathogen evasion strategies for this crucial host defense mechanism are not well understood.

Purpose of the Study:

  • To identify mechanisms by which pathogens evade the host inflammasome-pyroptosis pathway.
  • To investigate the role of Mycobacterium tuberculosis protein PtpB in modulating host immunity.

Main Methods:

  • Biochemical assays to determine PtpB's enzymatic activity as a phospholipid phosphatase.
  • Cellular experiments assessing the impact of PtpB on GSDMD localization and pyroptosis.
  • Genetic manipulation of PtpB to study its ubiquitin-binding and phosphatase functions.

Main Results:

  • Mycobacterium tuberculosis PtpB functions as a phospholipid phosphatase, targeting phosphatidylinositol-4-monophosphate and phosphatidylinositol-(4,5)-bisphosphate.
  • PtpB disrupts the membrane recruitment of cleaved GSDMD, inhibiting pyroptosis and cytokine release.
  • PtpB's phosphatase activity is dependent on its binding to ubiquitin.
  • Inhibition of PtpB's phosphatase activity or its ubiquitin-binding motif enhances host immune responses and reduces bacterial survival.

Conclusions:

  • Pathogens can evade host immunity by employing enzymes like PtpB to alter host cell membrane composition.
  • PtpB represents a novel virulence factor that suppresses the inflammasome-pyroptosis pathway.
  • Targeting PtpB or its interactions could be a strategy to enhance host defense against Mycobacterium tuberculosis.

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