Journal
JOURNAL OF VIROLOGY
Volume 88, Issue 9, Pages 5152-5164Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.03851-13
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Funding
- National Natural Science Foundation of China [81071860, 81172143, 81301943]
- Natural Science Foundation of Jiangsu Province of China [BK2010246]
- Fundamental Research Funds for the Central Universities [1093021412, 1112021402]
- State Key Laboratory of Pharmaceutical Biotechnology [KF-GN-201410]
- Scientific Foundation of Graduate School of Nanjing University
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The success of future clinical trials with oncolytic viruses depends on the identification and the control of mechanisms that modulate their therapeutic efficacy. In particular, little is known about the role of autophagy in infection by attenuated measles virus of the Edmonston strain (MV-Edm). We investigated the interaction between autophagy, innate immune response, and oncolytic activity of MV-Edm, since the antiviral immune response is a known factor limiting virotherapies. We report that MV-Edm exploits selective autophagy to mitigate the innate immune response mediated by DDX58/RIG-I like receptors (RLRs) in non-small cell lung cancer (NSCLC) cells. Both RNA interference (RNAi) and overexpression approaches demonstrate that autophagy enhances viral replication and inhibits the production of type I interferons regulated by RLRs. We show that MV-Edm unexpectedly triggers SQSTM1/p62-mediated mitophagy, resulting in decreased mitochondrion-tethered mitochondrial antiviral signaling protein (MAVS) and subsequently weakening the innate immune response. These results unveil a novel infectious strategy based on the usurpation of mitophagy leading to mitigation of the innate immune response. This finding provides a rationale to modulate autophagy in oncolytic virotherapy.
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