小柯机器人

美国波士顿儿童医院Judy Lieberman和Zhibin Zhang研究组合作取得一项新突破。他们发现Gasdermin E通过激活抗肿瘤免疫抑制肿瘤生长。相关论文于2020年3月11日在线发表在《自然》上。

研究人员发现在22种测试过的癌症相关GSDME突变中有20种突变降低了GSDME功能。研究人员发现小鼠中GSDME表达的肿瘤敲除Gsdme会增强肿瘤生长，而在Gsdme抑制的肿瘤中异位表达GSDME会抑制肿瘤生长。

这种肿瘤抑制作用是由杀伤性细胞毒性淋巴细胞所介导：在缺乏穿孔素或杀伤性淋巴细胞耗竭的小鼠中这种作用则消失。GSDME表达增强了肿瘤相关巨噬细胞对肿瘤细胞的吞噬作用，并增强了肿瘤浸润自然杀伤细胞和CD8 ⁺ T淋巴细胞的数量和功能。

杀伤细胞颗粒酶B还通过直接在caspase 3相同切割位点切割GSDME来激活靶细胞中不依赖caspase的细胞焦亡。不可切割或成孔肽段缺失的GSDME蛋白不能抑制肿瘤。因此，肿瘤GSDME通过激活细胞焦亡从而增强抗肿瘤免疫，以发挥抑癌作用。

据了解，gasdermin蛋白切割产生的氨基末端片段成孔会引起细胞焦亡（pyroptosis）。Gasdermin E（GSDME，也称为DFNA5）在家族性衰老相关的听力损伤中发生突变，其可以被caspase 3切割并且在表达GSDME的细胞中，将非炎性细胞凋亡转化为细胞焦亡。

在许多癌症中GSDME的表达均被抑制，在乳腺癌患者中，GSDME水平的降低与存活率降低相关，这表明GSDME可能是一种肿瘤抑制因子。

附：英文原文

Title: Gasdermin E suppresses tumour growth by activating anti-tumour immunity

Author: Zhibin Zhang, Ying Zhang, Shiyu Xia, Qing Kong, Shunying Li, Xing Liu, Caroline Junqueira, Karla F. Meza-Sosa, Temy Mo Yin Mok, James Ansara, Satyaki Sengupta, Yandan Yao, Hao Wu, Judy Lieberman

Issue&Volume: 2020-03-11

Abstract: Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis). Gasdermin E (GSDME, also known as DFNA5)—mutated in familial ageing-related hearing loss—can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer, 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.

DOI: 10.1038/s41586-020-2071-9

Source: https://www.nature.com/articles/s41586-020-2071-9

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