Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells

Science. 2020 May 29;368(6494):eaaz7548. doi: 10.1126/science.aaz7548. Epub 2020 Apr 16.

Abstract

Cytotoxic lymphocyte-mediated immunity relies on granzymes. Granzymes are thought to kill target cells by inducing apoptosis, although the underlying mechanisms are not fully understood. Here, we report that natural killer cells and cytotoxic T lymphocytes kill gasdermin B (GSDMB)-positive cells through pyroptosis, a form of proinflammatory cell death executed by the gasdermin family of pore-forming proteins. Killing results from the cleavage of GSDMB by lymphocyte-derived granzyme A (GZMA), which unleashes its pore-forming activity. Interferon-γ (IFN-γ) up-regulates GSDMB expression and promotes pyroptosis. GSDMB is highly expressed in certain tissues, particularly digestive tract epithelia, including derived tumors. Introducing GZMA-cleavable GSDMB into mouse cancer cells promotes tumor clearance in mice. This study establishes gasdermin-mediated pyroptosis as a cytotoxic lymphocyte-killing mechanism, which may enhance antitumor immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Granzymes / chemistry
  • Granzymes / metabolism*
  • HEK293 Cells
  • Humans
  • Interferon-gamma
  • Killer Cells, Natural / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Pore Forming Cytotoxic Proteins / chemistry
  • Pore Forming Cytotoxic Proteins / genetics
  • Pore Forming Cytotoxic Proteins / metabolism*
  • Protein Domains
  • Proteolysis
  • Pyroptosis / immunology*
  • T-Lymphocytes, Cytotoxic / enzymology*

Substances

  • GSDMB protein, human
  • Neoplasm Proteins
  • Pore Forming Cytotoxic Proteins
  • Interferon-gamma
  • Granzymes
  • GZMA protein, human