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Dr. Feng Shao’s group reveals that granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells

 

On May 29, 2020, Feng Shao’s group of National Institute of Biological Sciences, Beijingpublished the results of Granzyme A From Cytotoxic Lymphocytes Cleaves GSDMB to Trigger Pyroptosis in Target Cells in Science, revealing for the first time that Granzyme A (GZMA) cleaves Gasdermin B (GSDMB) to induce an important mechanism of pyroptosis, which provides new insights for tumor immunity.

Cytotoxic lymphocytes are a major class of immune effector cells and play an important role in the body's process of clearing viral infected or transformed cells. Cytotoxic lymphocyte-mediated immunity mainly depends on granzymes. Although the underlying mechanism is not fully understood, it is believed that granzymes kill target cells by inducing apoptosis. Understanding how cytotoxic lymphocytes use this approach to kill target cells is a central issue in immunology, especially considering the critical role of cytotoxic T lymphocytes (CTLs) in cancer immunotherapy.

Feng Shao’s group established NK-92MI cell killing assay and found that NK cells induce GSDMB-dependent pyroptosis via inter-domain cleavage of GSDMB. Further in vitro biochemical investigation showed that GSDMB is activated by GZMA through site-specific cleavage and its pore-forming activity is thus released, leading to pyroptosis. Importantly, they found that both GSDMB and GZMA are required for GZMA-GSDMB pathway-mediated pyroptosis. Interestingly, both interferon and TNF-α can upregulate GSDMB expression and promote GZMA-induced pyroptosis. Besides, the GZMA-GSDMB pathway is also critical for CTLs-mediated pyroptotic killing. Through the mouse tumor model, they proved that GZMA cleavage of GSDMB promotes tumor clearance in mice.

In summary, Feng Shao’s group reveals a new immune mechanism mediated by cytotoxic lymphocytes. Importantly, this study found that GSDMB acts downstream of granzymes, which highlights that protease such as caspase and granzymes are not essentially cell death executive proteins, and the Gasdermin protein family is the direct executor of pyroptosis. This suggests that different target cells, even when they are similarly recognized by the same type of cytotoxic lymphocytes, may experience different types of cell death. Therefore, future research on lymphocyte-mediated immune response should pay more attention to death-related events in target cells, rather than cell surface molecules such as PD-1.

Feng Shao of National Institute of Biological Sciences, Beijing is the corresponding author in this article, and Dr. Zhiwei Zhou and Huabin He in the laboratory are co-first authors.

Links: https://science.sciencemag.org/content/368/6494/eaaz7548.long