Gasdermin E suppresses tumour growth by activating anti-tumour immunity.
Zhibin Zhang,Zhibin Zhang,Ying Zhang,Ying Zhang,Shiyu Xia,Shiyu Xia,Qing Kong,Shunying Li,Xing Liu,Xing Liu,Xing Liu,Caroline Junqueira,Caroline Junqueira,Caroline Junqueira,Karla F. Meza-Sosa,Karla F. Meza-Sosa,Karla F. Meza-Sosa,Temy Mo Yin Mok,Temy Mo Yin Mok,Temy Mo Yin Mok,James Ansara,James Ansara,Satyaki Sengupta,Yandan Yao,Hao Wu,Hao Wu,Judy Lieberman,Judy Lieberman +27 more
TLDR
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.Abstract:
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 loss2—can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells3–5. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer2,6, 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.read more
Citations
More filters
Journal ArticleDOI
Ferroptosis, necroptosis, and pyroptosis in anticancer immunity
TL;DR: This review summarizes knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroPTosis, and pyroaptosis, which are the three potentially novel mechanisms of immunogenic cell death.
Journal ArticleDOI
Pyroptosis: mechanisms and diseases.
TL;DR: It is described that pyroptosis is a double-edged sword for tumors and the rational use of this dual effect will help to further explore the formation and development of tumors, and provide ideas for patients to develop new drugs based on pyroPTosis.
Journal ArticleDOI
PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis
Junwei Hou,Rongce Zhao,Rongce Zhao,Rongce Zhao,Weiya Xia,Chiung Wen Chang,Yun You,Jung Mao Hsu,Jung Mao Hsu,Lei Nie,Yeh Chen,Yu Chuan Wang,Chunxiao Liu,Wei Jan Wang,Wei Jan Wang,Yun Wu,Baozhen Ke,Jennifer L. Hsu,Kebin Huang,Kebin Huang,Zu Ye,Yi Yang,Xianghou Xia,Yintao Li,Chia Wei Li,Bin Shao,Bin Shao,John A. Tainer,Mien Chie Hung,Mien Chie Hung,Mien Chie Hung +30 more
TL;DR: Findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/Caspas-8 mediates non-canonical pyroptosis pathway in cancer cells, causing tumor necrosis.
Journal ArticleDOI
Emerging connectivity of programmed cell death pathways and its physiological implications
TL;DR: The intriguing notion that the different types of PCD could be seen as a single, coordinated cell death system, in which the individual pathways are highly interconnected and can flexibly compensate for one another is discussed.
Journal ArticleDOI
Targeting immunogenic cell death in cancer
Asma Ahmed,Stephen W.G. Tait +1 more
TL;DR: The cell death modalities connected to ICD, the DAMPs exposed during ICD and the mechanism by which they activate the immune system are discussed, and the therapeutic potential and challenges of harnessing ICD in cancer immunotherapy are discussed.
References
More filters
Journal ArticleDOI
Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells
Ophir Shalem,Ophir Shalem,Neville E. Sanjana,Neville E. Sanjana,Ella Hartenian,Xi-Shun Shi,David A. Scott,David A. Scott,Tarjei S. Mikkelsen,Dirk Heckl,Benjamin L. Ebert,David E. Root,John G. Doench,Feng Zhang,Feng Zhang +14 more
TL;DR: This work shows that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells, and observes a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation.
Journal ArticleDOI
Improved vectors and genome-wide libraries for CRISPR screening.
TL;DR: In this paper, Zhang et al. used a Genome-scale CRISPR Knock-Out (GeCKO) library to identify loss-of-function mutations in a melanoma model.
Journal ArticleDOI
Immunogenic cell death in cancer and infectious disease
TL;DR: Current knowledge on the mechanisms that underlie the activation of immune responses against dying cells and their pathophysiological relevance are reviewed.
Journal ArticleDOI
Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin
TL;DR: It is shown that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis, suggesting that casp enzyme activation can trigger necrosis by cleaving G SDME and offer new insights into cancer chemotherapy.
Journal ArticleDOI
Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death.
Corey Rogers,Teresa Fernandes-Alnemri,Lindsey Mayes,Diana Alnemri,Gino Cingolani,Emad S. Alnemri +5 more
TL;DR: This work shows that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necroticDFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis, and provides a molecular mechanism forsecondary necrosis.
Related Papers (5)
Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling
Nobuhiko Kayagaki,Irma B. Stowe,Bettina L. Lee,Karen O'Rourke,Keith R. Anderson,Søren Warming,Trinna L. Cuellar,Benjamin Haley,Merone Roose-Girma,Qui T. Phung,Peter Liu,Jennie R. Lill,Hong Li,Jiansheng Wu,Sarah K. Kummerfeld,Juan Zhang,Wyne P. Lee,Scott J. Snipas,Guy S. Salvesen,Lucy X. Morris,Linda Fitzgerald,Yafei Zhang,Edward M. Bertram,Christopher C. Goodnow,Christopher C. Goodnow,Christopher C. Goodnow,Vishva M. Dixit +26 more