A tumour necrosis factor receptor-like protein encoded by Singapore grouper iridovirus modulates cell proliferation, apoptosis and viral replication.

Yepin Yu,Youhua Huang,Shina Wei,Lingli Zhou,Xiaohong Huang,Songwei Ni,Qiwei Qin,Pengfei Li

doi:10.1099/jgv.0.000379

Abstract

It has been demonstrated that tumour necrosis factor receptor (TNFR) homologues encoded by viruses are usually involved in virus immune evasion by regulating the host immune response or mediating apoptotic cell death. Here, a novel TNFR-like protein encoded by Singapore grouper iridovirus (SGIV VP51) was cloned and characterized. Amino acid analysis showed that VP51 contained three cysteine-rich domains (CRDs) and a transmembrane domain at its C terminus. The expression of VP51 in vitro enhanced cell proliferation, and affected cell cycle progression via altering the G1/S transition. Furthermore, VP51 overexpression improved cell viability during SGIV infection via inhibiting virus-induced apoptosis, evidenced by the reduction of apoptotic bodies and the decrease of caspase-3 activation. In addition, overexpression of VP51 increased viral titre and the expression of viral structural protein gene MCP and cell proliferation promoting gene ICP-18. In contrast, the expression of the viral apoptosis inducing gene, LITAF, was significantly decreased. Although all three CRDs were essential for the action of VP51, CRD2 and CRD3 exerted more crucial roles on virus-induced apoptosis, viral gene transcription and virus production, while CRD1 was more crucial for cell proliferation. Together, SGIV TNFR-like products not only affected cell cycle progression and enhanced cell growth by increasing the expression of the virus encoded cell proliferation gene, but also inhibited virus-induced apoptotic cell death by decreasing the expression of the viral apoptosis inducing gene. Our results provided new insights into understanding the underlying mechanism by which iridovirus regulated the apoptotic pathway to complete its life cycle.

Highlights

Apoptosis plays a significant role in the immune response by eliminating cells that might be harmful to the host, and several functional viral genes are employed to regulate apoptosis in the host to enhance the production of progeny (Hong et al, 2002; Roulston et al, 1999)
Sequence analysis revealed that the deduced amino acid sequence of VP51 contained a transmembrane domain at its C terminus and three extracellular cysteine-rich domains (CRDs) with six, six and seven conserved cysteine residues, respectively (Fig. 1)
The different numbers of CRDs in VP51 and VP96 indicated that VP51 was a novel viral tumour necrosis factor receptor (TNFR)-like protein encoded by Singapore grouper iridovirus (SGIV) (Huang et al, 2013)

Summary

Introduction

Apoptosis plays a significant role in the immune response by eliminating cells that might be harmful to the host, and several functional viral genes are employed to regulate apoptosis in the host to enhance the production of progeny (Hong et al, 2002; Roulston et al, 1999). Increasing evidence has revealed that viruses encode several tumour necrosis factor receptor (TNFR) homologues to evade the host immune system (Rahman & McFadden, 2006). It has already been reported that the T2 protein encoded by the myxoma virus (M-T2) is a TNFR-like protein that has two distinct activities: secreted M-T2 binds and inhibits rabbit tumour necrosis factor alpha (TNF-a), while intracellular M-T2 blocks virus-induced lymphocyte apoptosis (Sedger et al, 2006). The function of viral TNFR homologues in lower vertebrate viruses remains largely unknown. The lymphocystis disease viruses (LDVs), LDVICp016, LDVICp95 and LDVICp167 have been characterized as TNFR homologues that do not have a TNFR-like function (Pontejo et al, 2013). Singapore grouper iridovirus (SGIV) is a novel Ranavirus isolated from diseased grouper

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Results

Conclusion