Cytoplasmic Translocation of Nucleolar Protein NOP53 Promotes Viral Replication by Suppressing Host Defense

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.

Longitudinal analysis of influenza vaccination implicates regulation of RIG-I signaling by DNA methylation

“…NOP53 is a tumor suppressor protein that translocates to the cytoplasm during viral infection. It was previously found to remove K63-linked ubiquitination, which leads to the decreased transcription of type 1 interferons (23). NPLO4 is involved in K48-linked polyubiquitin modi cation-dependent protein binding activity (24), which also negatively regulates the production of type 1 interferons.…”

“…BIRC2 is an E3 ubiquitin-protein ligase; it functions as a repressor of the NF-kB pathway (28), which itself is positively regulated by RIG-1 signaling (29). TRIM15 is a RIG-I-like receptor protein regulator required for RIG-I signaling and downstream type-1 interferon production (23,30). SEC14L, GPATCH3 and C1QBP compete or interact with virus-induced signaling adaptor molecules (VISA), and can disrupt the assembly of virus-induced VISA signalosomes which negatively regulate the RIG-I signaling pathway (31)(32)(33).…”

Longitudinal analysis of influenza vaccination implicates regulation of RIG-I signaling by DNA methylation

“…NOP53 is a tumor suppressor protein that translocates to the cytoplasm during viral infection. It was previously found to remove K63-linked ubiquitination, which leads to the decreased transcription of type 1 interferons 32 . NPLO4 is involved in K48-linked polyubiquitin modification-dependent protein binding activity 33 , which also negatively regulates the production of type 1 interferons.…”

Lytic Reactivation of the Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) Is Accompanied by Major Nucleolar Alterations

“…This was associated with extensive redistribution of the nucleolar protein UBF, which normally resides at the nucleolar FC substructure. The RNA polymerase I transcription factor UBF, the large RNA polymerase I subunit RPA194, and the vBcl-2 nucleolar partner PICT-1 [58], which also functions in ribosomal biogenesis and in attenuation of the interferon response [86,99], concomitantly redistributed and colocalized in dot-like structures. The RNA methyltransferase Fibrillarin presented a few large foci surrounded by dense chromatin, and only partially colocalized with UBF.…”