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

TLDR

Cytotoxic lymphocyte immunity depends on granzymes, which are believed to kill target cells via apoptosis but whose exact mechanisms remain unclear, and gasdermin B is highly expressed in digestive tract epithelia and related tumors. The study reports that natural killer cells and cytotoxic T lymphocytes eliminate GSDMB‑positive cells through pyroptosis. The mechanism involves granzyme A cleaving GSDMB, thereby activating its pore‑forming activity to trigger pyroptosis. The findings demonstrate that IFN‑γ up‑regulates GSDMB and promotes pyroptosis, that expressing GZMA‑cleavable GSDMB in mouse tumors enhances clearance, and that gasdermin‑mediated pyroptosis is a key cytotoxic lymphocyte killing mechanism that could boost antitumor immunity.

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.