A picorna-like virus suppresses the N-end rule pathway to inhibit apoptosis.

Zhaowei Wang,Di Wu,Xueli Yang,Xueyi Zhang,Yang Qiu,Yujie Liu,Yongxiang Liu,Xiaoling Xia,Yuan Fang,Jiuyue Xu,Xi Zhou

doi:10.7554/elife.30590

Zhaowei Wang, Di Wu + Show 9 more

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https://doi.org/10.7554/elife.30590

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Abstract

The N-end rule pathway is an evolutionarily conserved proteolytic system that degrades proteins containing N-terminal degradation signals called N-degrons, and has emerged as a key regulator of various processes. Viruses manipulate diverse host pathways to facilitate viral replication and evade antiviral defenses. However, it remains unclear if viral infection has any impact on the N-end rule pathway. Here, using a picorna-like virus as a model, we found that viral infection promoted the accumulation of caspase-cleaved Drosophila inhibitor of apoptosis 1 (DIAP1) by inducing the degradation of N-terminal amidohydrolase 1 (NTAN1), a key N-end rule component that identifies N-degron to initiate the process. The virus-induced NTAN1 degradation is independent of polyubiquitylation but dependent on proteasome. Furthermore, the virus-induced N-end rule pathway suppression inhibits apoptosis and benefits viral replication. Thus, our findings demonstrate that a virus can suppress the N-end rule pathway, and uncover a new mechanism for virus to evade apoptosis.

Highlights

Apoptosis is a highly conserved biological process throughout evolution and is important for normal tissue development and removal of obsolete, abnormal or potentially harmful cells
Previous studies showed that various viruses, including Autographa californica nucleopolyhedrovirus (AcMNPV), Flock House Virus (FHV), and Drosophila C virus (DCV), can induce apoptosis in Drosophila cells or adult flies (Lamiable et al, 2016; Lannan et al, 2007; Liu et al, 2013; Nainu et al, 2015; Settles and Friesen, 2008)
Our results showed that the ectopic expression of Drosophila inhibitor of apoptosis 1 (DIAP1) effectively inhibited apoptosis (Figure 2A) and caused about two-fold increase of DCV genomic RNA (Figure 2B)

Summary

Introduction

Apoptosis is a highly conserved biological process throughout evolution and is important for normal tissue development and removal of obsolete, abnormal or potentially harmful cells. The apoptotic pathway shows sensitivity to various stimuli and can lead to cysteinyl aspartate protease (caspase) dependent proteolytic digestion and further cell death (Benedict et al, 2002; Kumar, 2007). Various viruses, including vertebrate and invertebrate viruses, can induce apoptosis in infected cells or organisms (Everett and McFadden, 1999; Lamiable et al, 2016; Lannan et al, 2007; Liu et al, 2013; Nainu et al, 2015; Settles and Friesen, 2008). The fly caspase-9 homolog Dronc is the only known initiator caspase that is activated following a variety of apoptotic stimuli and can be activated by auto-cleavage (Muro et al, 2004). Activated Dronc can further cleave and activate various effector caspases such as DrICE and DCP-1, leading to apoptotic induction.

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