Abstract
NOP53 is a tumor suppressor protein located in the nucleolus and is translocated to the cytoplasm during infection by vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1), as shown in our previous study. Cytoplasmic NOP53 interacts with the retinoic acid-inducible gene I (RIG-I) to remove its K63-linked ubiquitination, leading to attenuation of type I interferon IFN-β. In the present study, we found no obvious translocation of NOP53 in infection by a mutant virus lacking ICP4 (HSV-1/d120, replication inadequate). Blocking cytoplasmic translocation of NOP53 by the deletion of its nuclear export sequence (NES) abrogated its ability to support viral replication. These results demonstrated that NOP53 redistribution is related to viral replication. It is interesting that treatment with poly (I:C) or RIG-I-N (a constitutively-active variant) directly induced NOP53 cytoplasmic translocation. To better assess the function of cytoplasmic NOP53 in viral replication, the NOP53-derived protein N3-T, which contains a human immunodeficiency virus (HIV)-derived cell-penetrating Tat peptide at the C-terminal region of N3 (residues 330–432), was constructed and expressed. The recombinant N3-T protein formed trimers, attenuated the expression of IFN-β and IFN-stimulated genes, as well as decreased the phosphorylation level of interferon regulatory factor 3 (IRF3). Furthermore, N3-T promoted the efficient replication of enveloped and non-enveloped DNA and RNA viruses belonging to 5 families. Our findings expand the understanding of the mechanism by which viruses utilize the nucleolar protein NOP53 for optimal viral replication.
Highlights
Innate immunity is critical for defending the host from pathogens, and type I interferon (IFN)is the core of the cellular antiviral response [1,2,3,4,5]
It is reported that cytoplasmic translocation of NOP53 has an important function in vesicular stomatitis virus (VSV)
NOP53 translocation is caused by viral replication, cells were infected with an inadequate replication virus—ICP4 deletion mutant virus herpes simplex virus type 1 (HSV-1)/d120
Summary
Innate immunity is critical for defending the host from pathogens, and type I interferon (IFN)is the core of the cellular antiviral response [1,2,3,4,5]. Viral infections produce highly conserved pathogen-associated molecular patterns (PAMPs) such as double-stranded RNA (dsRNA). RIG-I, a member of the RIG-I-like receptor (RLR) family, interacts with viral RNA and recruits mitochondrial-associated virus stimulators MAVS recruits tumor necrosis receptor-associated factor 3 (TRAF3), which causes TRAF3 lysine 63 (K63)-linked auto-ubiquitination to provide docking sites for the TANK binding kinase 1/I kappa-B kinase epsilon (TBK1/IKKε) complex [9,10,11]. This complex undergoes auto-phosphorylation-mediated activation, resulting in phosphorylation and activation of the type I
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