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Abstract
Autophagy is a cellular response to starvation that generates autophagosomes to carry long-lived proteins and cellular organelles to lysosomes for degradation. Activation of autophagy by viruses can provide an innate defense against infection, and for (+) strand RNA viruses autophagosomes can facilitate assembly of replicase proteins. We demonstrated that nonstructural protein (NSP) 6 of the avian coronavirus, infectious bronchitis virus (IBV), generates autophagosomes from the ER. A statistical analysis of MAP1LC3B puncta showed that NSP6 induced greater numbers of autophagosomes per cell compared with starvation, but the autophagosomes induced by NSP6 had smaller diameters compared with starvation controls. Small diameter autophagosomes were also induced by infection of cells with IBV, and by NSP6 proteins of MHV and SA RS and NSP5, NSP6, and NSP7 of arterivirus PRRSV. Analysis of WIPI2 puncta induced by NSP6 suggests that NSP6 limits autophagosome diameter at the point of omegasome formation. IBV NSP6 also limited autophagosome and omegasome expansion in response to starvation and Torin1 and could therefore limit the size of autophagosomes induced following inhibition of MTOR signaling, as well as those induced independently by the NSP6 protein itself. MAP1LC3B-puncta induced by NSP6 contained SQSTM1, which suggests they can incorporate autophagy cargos. However, NSP6 inhibited the autophagosome/lysosome expansion normally seen following starvation. Taken together the results show that coronavirus NSP6 proteins limit autophagosome expansion, whether they are induced directly by the NSP6 protein, or indirectly by starvation or chemical inhibition of MTOR signaling. This may favor coronavirus infection by
compromising the ability of autophagosomes to deliver viral components to lysosomes for degradation.
compromising the ability of autophagosomes to deliver viral components to lysosomes for degradation.
Original language | English |
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Pages (from-to) | 1426-1441 |
Number of pages | 16 |
Journal | Autophagy |
Volume | 10 |
Issue number | 8 |
Early online date | 11 Jun 2014 |
DOIs | |
Publication status | Published - 1 Aug 2014 |
Keywords
- autophagosome quantification
- autophagy
- coronavirus
- MHV
- nonstructural proteins
- omegasome
- SARS
Profiles
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Tom Wileman
- Norwich Medical School - Research Leader
- Metabolic Health - Member
- Gastroenterology and Gut Biology - Member
Person: Research Group Member, Academic, Teaching & Research
Projects
- 1 Finished