The autophagy protein ATG16L1 is required for Sindbis virus-induced eIF2α phosphorylation and stress granule formation

Jefferson, Matthew, Bone, Benjamin, Buck, Jasmine L. and Powell, Penny P. (2019) The autophagy protein ATG16L1 is required for Sindbis virus-induced eIF2α phosphorylation and stress granule formation. Viruses, 12 (1). ISSN 1999-4915

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Abstract

Sindbis virus (SINV) infection induces eIF2α phosphorylation, which leads to stress granule (SG) assembly. SINV infection also stimulates autophagy, which has an important role in controlling the innate immune response. The importance of autophagy to virus-induced translation arrest is not well understood. In this study, we show that the autophagy protein ATG16L1 not only regulates eIF2α phosphorylation and the translation of viral and antiviral proteins, but also controls SG assembly. Early in infection (2hpi), capsids were recruited by host factors Cytotoxic Granule-Associated RNA Binding Protein (TIA1), Y-box binding protein 1 (YBX1), and vasolin-containing protein 1 (VCP), to a single perinuclear body, which co-localized with the viral pattern recognition sensors, double stranded RNA-activated protein-kinase R (PKR) and RIG-I. By 6hpi, there was increased eIF2α phosphorylation and viral protein synthesis. However, in cells lacking the autophagy protein ATG16L1, SG assembly was inhibited and capsid remained in numerous small foci in the cytoplasm containing YBX1, TIA1 with RIG-I, and these persisted for over 8hpi. In the absence of ATG16L1, there was little phosphorylation of eIF2α and low levels of viral protein synthesis. Compared to wild type cells, there was potentiated interferon protein and interferon-stimulated gene (ISG) mRNA expression. These results show that ATG16L1 is required for maximum eIF2α phosphorylation, proper SG assembly into a single perinuclear focus, and for attenuating the innate immune response. Therefore, this study shows that, in the case of SINV, ATG16L1 is pro-viral, required for SG assembly and virus replication.

Item Type: Article
Uncontrolled Keywords: autophagy,eif2α,interferon,rna binding proteins,sindbis virus,stress granule,infectious diseases,virology ,/dk/atira/pure/subjectarea/asjc/2700/2725
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School

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Depositing User: LivePure Connector
Date Deposited: 25 Jan 2020 03:33
Last Modified: 18 Mar 2020 14:21
URI: https://ueaeprints.uea.ac.uk/id/eprint/73782
DOI: 10.3390/v12010039

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