RIPK3 promotes adenovirus type 5 activity
File(s)
Published version
Supporting information
Author(s)
Type
Journal Article
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.
Date Issued
2017-12-13
Date Acceptance
2017-10-30
Citation
Cell Death and Disease, 2017, 8 (12)
ISSN
2041-4889
Publisher
Nature Publishing Group
Journal / Book Title
Cell Death and Disease
Volume
8
Issue
12
Copyright Statement
© The Author(s). 2017. his article is licensed under a Creative Commons Attribution 4.0 Internat
ional License, which permits use, sharing, adaptation, distribution and
reproduction
in any medium or format, as long as you give appropriate credit to the origina
l author(s) and the source, provide a li
nktotheCreativeC
ommons license,
and indicate if
changes were made. The images or other third party material in this article are included in the article
’
s Creative Commons license, unless indicated
otherwise in a credit line to the material. If
material is not included in the article
’
s Creative Commons license and your intended use is not permitted by sta
tutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright hol
der. To view a copy of this license, visit
http://creativecommons
.org/licenses/by/4.0/
ional License, which permits use, sharing, adaptation, distribution and
reproduction
in any medium or format, as long as you give appropriate credit to the origina
l author(s) and the source, provide a li
nktotheCreativeC
ommons license,
and indicate if
changes were made. The images or other third party material in this article are included in the article
’
s Creative Commons license, unless indicated
otherwise in a credit line to the material. If
material is not included in the article
’
s Creative Commons license and your intended use is not permitted by sta
tutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright hol
der. To view a copy of this license, visit
http://creativecommons
.org/licenses/by/4.0/
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/29238045
PII: 10.1038/s41419-017-0110-8
Publication Status
Published
Coverage Spatial
England
Article Number
ARTN 3206