A new mechanism of interferon's antiviral action: Induction of autophagy, essential for paramyxovirus replication, is inhibited by the interferon stimulated gene, TDRD7.

Gayatri Subramanian,Ritu Chakravarti,Manoj Veleeparambil,Ying Zhang,Cara Beate Peter,Saurabh Chattopadhyay,Teodora Kuzmanovic,Ganes C Sen,Christopher F Basler

doi:10.1371/journal.ppat.1006877

Gayatri Subramanian, Ritu Chakravarti + Show 7 more

Open Access

https://doi.org/10.1371/journal.ppat.1006877

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Abstract

The interferon (IFN) system represents the first line of defense against a wide range of viruses. Virus infection rapidly triggers the transcriptional induction of IFN-β and IFN Stimulated Genes (ISGs), whose protein products act as viral restriction factors by interfering with specific stages of virus life cycle, such as entry, transcription, translation, genome replication, assembly and egress. Here, we report a new mode of action of an ISG, IFN-induced TDRD7 (tudor domain containing 7) inhibited paramyxovirus replication by inhibiting autophagy. TDRD7 was identified as an antiviral gene by a high throughput screen of an ISG shRNA library for blocking IFN’s protective effect against Sendai virus (SeV) replication. The antiviral activity of TDRD7 against SeV, human parainfluenza virus 3 and respiratory syncytial virus was confirmed by its genetic ablation or ectopic expression in several types of mouse and human cells. TDRD7’s antiviral action was mediated by its ability to inhibit autophagy, a cellular catabolic process which was robustly induced by SeV infection and required for its replication. Mechanistic investigation revealed that TDRD7 interfered with the activation of AMP-dependent kinase (AMPK), an enzyme required for initiating autophagy. AMPK activity was required for efficient replication of several paramyxoviruses, as demonstrated by its genetic ablation or inhibition of its activity by TDRD7 or chemical inhibitors. Therefore, our study has identified a new antiviral ISG with a new mode of action.

Highlights

Interferon (IFN) system provides the first line of immune defense against viral infections in vertebrates [1,2,3]
In each well of cells, all IFN Stimulated Genes (ISGs) were induced by IFN-β-pretreatment but the expression of only one of them was prevented by transduction of the cognate shRNA; the cells were infected with Sendai virus (SeV) and the degree of virus replication was measured
The results indicate that knockdown of IRF9 reversed the IFN-β-mediated inhibition of SeV replication (Fig 1B)

Summary

Introduction

Interferon (IFN) system provides the first line of immune defense against viral infections in vertebrates [1,2,3]. The Pattern Recognition Receptors (PRRs), e.g. Toll Like Receptors (TLRs), RIG-I Like Receptors (RLRs) and cyclic AMP-GMP synthase (cGAS)/stimulator of IFN genes (STING), are located in distinct cellular compartments, to sense specific viral components, such as the viral nucleic acids [4,5,6,7,8,9]. The co-operative action of these transcription factors triggers the synthesis of Type-I interferons e.g. IFN-β, an extensively studied antiviral cytokine. After synthesis in the infected cells, IFN-β is secreted and acts on the infected as well as yet uninfected cells via Janus Kinase (JAK)/Signal Transducer of Transcription (STAT) signaling pathways to trigger the synthesis of a number of antiviral genes

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