Gasdermin E suppresses tumour growth by activating anti-tumour immunity
Gasdermin E suppresses tumour growth by activating anti-tumour immunity
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DOI：
10.1038/s41586-020-2071-9
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发表时间：
2020-03-11
期刊：
影响因子：
64.8
通讯作者：
Lieberman, Judy
中科院分区：
文献类型：
--
作者：
Zhang, Zhibin;Zhang, Ying;Lieberman, Judy
裂解Gasdermin蛋白产生形成孔的氨基末端片段会导致炎性细胞死亡(热下垂)(1)。Gasdermin E(GSDME，也称为DFNA5)--在家族性老年性听力损失中突变(2)--可被caspase 3切割，从而在表达GSDME的细胞中将非炎症性细胞凋亡转化为嗜热性细胞凋亡(3-5)。在许多癌症中，GSDME的表达被抑制，GSDME水平的降低与乳腺癌(2，6)导致的生存率下降有关，这表明GSDME可能是一种肿瘤抑制因子。在这里，我们显示了22个与癌症相关的GSDME突变中的20个降低了GSDME的功能。在小鼠中，在表达GSDME的肿瘤中敲除Gsdme会增强作用，而在Gsdme抑制的肿瘤中异位表达会抑制肿瘤的生长。这种肿瘤抑制是由杀伤细胞毒性淋巴细胞介导的：在穿孔素缺乏的小鼠或缺乏杀伤淋巴细胞的小鼠中，这种抑制作用被取消。GSDME的表达增强了肿瘤相关巨噬细胞对肿瘤细胞的吞噬功能，以及肿瘤浸润性自然杀伤细胞和CD8(+)T淋巴细胞的数量和功能。杀伤细胞颗粒酶B还通过在与caspase 3相同的位置直接切割GSDME来激活靶细胞中caspase非依赖性的下垂。未切割或孔洞缺陷的GSDME蛋白不具有肿瘤抑制作用。Gasdermin E蛋白作为肿瘤抑制因子，被caspase 3和颗粒酶B所裂解，导致癌细胞上睑下垂，引发对肿瘤的免疫反应。
Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis)(1). Gasdermin E (GSDME, also known as DFNA5)-mutated in familial ageing-related hearing loss(2)-can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells(3-5). GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer(2,6), suggesting that GSDME might be a tumour suppressor. Here we show that 20 of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes: it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as the number and functions of tumour-infiltrating natural-killer and CD8(+) T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity.The gasdermin E protein is shown to act as a tumour suppressor: it is cleaved by caspase 3 and granzyme B and leads to pyroptosis of cancer cells, provoking an immune response to the tumour.