Research Article

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

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Science  29 May 2020:
Vol. 368, Issue 6494, eaaz7548
DOI: 10.1126/science.aaz7548

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  • RE: Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells
    • Dr Dianne Sika-Paotonu CQS MRSNZ, Associate Dean (Pacific)/Senior Lecturer Pathology & Molecular Medicine, Wellington School of Medicine & Health Sciences, University of Otago, New Zealand

    To the Editor,

    I read with keen interest the article by Zhou et al., (1) and titled “Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells”.

    This work sought to determine whether any members of the gasdermin family of pore-forming proteins were responsive to serine protease granzymes and might induce death in target cells.

    The authors showed that of the gasdermins tested, Gasdermin B (GSDMB) alone in human embryonic kidney (HEK) 293T cells induced pyroptotic killing after granzyme induced cleavage of the interdomain linker of GSDMB.

    Natural killer cells (NK) and cytotoxic T lymphocytes (CTLs) were the source of granzyme A (GZMA) that cleaved and activated GSDMB at Lys244 within the interdomain linker, promoting the pore-forming activity of GSDMB, a key component of the pyroptotic pathway and responsible for this highly proinflammatory type of cell death - also described as gasdermin-mediated programmed necrosis.

    The authors also showed elevated GSDMB expression in selected tissues such as the digestive tract epithelia, including derived tumors, and interferon-γ could actually upregulate GSDMB expression and induce GZMA-induced pyroptosis.

    That the introduction of GZMA-cleavable GSDMB into mouse cancer cells induced tumor clearance in their murine model, was also of clinical relevance, in addition to the selected expression of GSDMB identified only in certain tissues, highlighting the importance...

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    Competing Interests: None declared.

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