Weigert, M. et al. (2017) RIPK3 promotes adenovirus type 5 activity. Cell Death and Disease, 8, 3206. (doi: 10.1038/s41419-017-0110-8) (PMID:29238045) (PMCID:PMC5870599)
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Abstract
Oncolytic adenoviral mutants infect human malignant cells and replicate selectively within them. This induces direct cytotoxicity that can also trigger profound innate and adaptive immune responses. However, the mechanism by which adenoviruses produce cell death remains uncertain. We previously suggested that type 5 adenoviruses, including the E1A CR2 deletion mutant dl922-947, might induce a novel form of programmed death resembling necroptosis. Here we have investigated the roles of core necrosis proteins RIPK1, RIPK3 and MLKL in the cytotoxicity of dl922-947 and other adenovirus serotypes. By electron microscopy, we show that dl922-947 induces similar necrotic morphology as TSZ treatment (TNF-α, Smac mimetic, zVAD.fmk). However, dl922-947-mediated death is independent of TNF-α signalling, does not require RIPK1 and does not rely upon the presence of MLKL. However, inhibition of caspases, specifically caspase-8, induces necroptosis that is RIPK3 dependent and significantly enhances dl922-947 cytotoxicity. Moreover, using CRISPR/Cas9 gene editing, we demonstrate that the increase in cytotoxicity seen upon caspase inhibition is also MLKL dependent. Even in the absence of caspase inhibition, RIPK3 expression promotes dl922-947 and wild-type adenovirus type 5 efficacy both in vitro and in vivo. Together, these results suggest that adenovirus induces a form of programmed necrosis that differs from classical TSZ necroptosis.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Blyth, Professor Karen and Leung, Dr Elaine and Dowson, Miss Suzanne and Orange, Miss Clare and Yu, Miss Xinzi and Ennis, Dr Darren and Binks, Alex and Weigert, Melanie and Walton, Miss Josephine and Mcneish, Professor Iain and Athineos, Mr Dimitris and Tait, Professor Stephen and Mullin, Mrs Margaret |
| Authors: | Weigert, M., Binks, A., Dowson, S., Leung, E. Y.L., Athineos, D., Yu, X., Mullin, M., Walton, J. B., Orange, C., Ennis, D., Blyth, K., Tait, S. W.G., and McNeish, I. A. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Cell Death and Disease |
| Publisher: | Nature Publishing Group |
| ISSN: | 2041-4889 |
| ISSN (Online): | 2041-4889 |
| Published Online: | 13 December 2017 |
| Copyright Holders: | Copyright © 2017 The Authors |
| First Published: | First published in Cell Death and Disease 8: 3206 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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