國家衛生研究院 NHRI:Item 3990099045/14760

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Title:	Zika virus cleaves GSDMD to disseminate prognosticable and controllable oncolysis in a human glioblastoma cell model
Authors:	Kao, YT;Wang, HI;Shie, CT;Lin, CF;Lai, MMC;Yu, CY
Contributors:	National Institute of Infectious Diseases and Vaccinology
Abstract:	Glioblastoma (GBM) is the most common aggressive malignant brain cancer and is chemo- and radioresistant, with poor therapeutic outcomes. The “double-edged sword” of virus-induced cell death could be a potential solution if the oncolytic virus specifically kills cancer cells but spares normal ones. Zika virus (ZIKV) has been defined as a prospective oncolytic virus by selectively targeting GBM cells, but unclear understanding of how ZIKV kills GBM and the consequences hinders its application. Here, we found that the cellular gasdermin D (GSDMD) is required for the efficient death of a human GBM cell line caused by ZIKV infection. The ZIKV protease specifically cleaves human GSDMD to activate caspase-independent pyroptosis, harming both viral protease-harboring and naive neighboring cells. Analyzing human GSDMD variants showed that most people were susceptible to ZIKV-induced cytotoxicity, except for those with variants that resisted ZIKV cleavage or were defective in oligomerizing the N terminus GSDMD cleavage product. Consistently, ZIKV-induced secretion of the pro-inflammatory cytokine interleukin-1β and cytolytic activity were both stopped by a small-molecule inhibitor targeting GSDMD oligomerization. Thus, potential ZIKV oncolytic therapy for GBM would depend on the patient's GSDMD genetic background and could be abolished by GSDMD inhibitors if required.
Date:	2023-03-16
Relation:	Molecular Therapy - Oncolytics. 2023 Mar 16;28:104-117.
Link to:	http://dx.doi.org/10.1016/j.omto.2022.12.008
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2372-7705&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000973491100001
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85146166637
Appears in Collections:	[Chia-Yi Yu] Periodical Articles

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