Nucleophosmin (NPM1 also known as B23 numatrin or NO38) is a

Nucleophosmin (NPM1 also known as B23 numatrin or NO38) is a pentameric RNA-binding protein with RNA and protein chaperon functions. proteins. Both viral proteins show in mechanistically different modes high affinity for a binding site on the N-terminal oligomerization domain of NPM1. Rev additionally exhibits low-affinity for the central histone-binding domain of Luseogliflozin NPM1. We also showed that the proapoptotic cyclic peptide CIGB-300 specifically binds to NPM1 oligomerization domain and blocks its association with Rev and US11. Moreover HIV-1 virus production was significantly reduced in the cells treated with CIGB-300. Results of this study suggest that targeting NPM1 may represent a useful approach for antiviral intervention. Introduction Nucleophosmin (NPM1 also known as B23 numatrin NO38) is a multifunctional phosphoprotein predominantly localized in the nucleoli which participates extensively in RNA regulatory mechanisms including transcription ribosome assembly and biogenesis mRNA stability translation and microRNA processing [1 2 NPM1 (294 amino acids; 37 kDa) consists of an N-terminal oligomerization domain (OD) a central histone binding domain (HBD) and a C-terminal RNA-binding domain (RBD) (Fig 1A) [3]. It also contains nuclear localization signals (NLSs) at the N-terminus central nuclear exports signals (NESs) and a nucleolar localization signal (NoLS) at the very C-terminus (Fig 1A). NPM1 shuttles between the nucleus and cytoplasm and accordingly a proportion of nucleolar NPM1 constantly translocates to the nucleoplasm and inner nuclear membrane as well as to the cytoplasm and inner and Luseogliflozin outer plasma membrane [2 4 5 Due to this ability NPM1 has been implicated in many stages of viral infection through interaction with a multitude of proteins from heterologous viruses (Table 1) including Human immunodeficiency virus type 1 (HIV-1) Rev [4] Human T-cell leukemia virus type 1 (HTLV-1) Rex [6] and Herpes simplex virus type 1 (HSV-1) UL24 [7]. Fig 1 Schematic representation of domain organization various constructs and proteins of NPM1 HSV-1 US11 and HIV-1 Rev. Table 1 Nucleophosmin involvement in multiple viral infections. Rev is 116 amino acid long and its RNA-binding domain is Rabbit Polyclonal to GPR137C. composed of an arginine-rich motif (ARM) which binds to various HIV-1 RNA stem loop structures [8]. The RNA- binding domain of Rev also acts as a nuclear/nucleolar targeting signal which can deliver cytoplasmic proteins to the nucleus or nucleolus [8 9 Many host proteins Luseogliflozin including DDX1 DDX3 eIF5A exportin-1 hRIP/Rab Matrin-3 NPM1 PIMT and RNA helicase A have been suggested to bind to Rev prior to induction of its nuclear translocation [10-13]. NPM1 interaction with Rev appears to be necessary for nucleolar localization of Rev [4]. In fact the HIV-1 Rev response Luseogliflozin element a segment of viral RNA represents a nuclear export signal which triggers Rev binding the nucleocytoplasmic shuttling of viral transcripts in infected cells [14]. A similar mechanism is controlled by Rex Luseogliflozin responsive element [15]. Most interestingly US11 a protein of HSV-1 has the potential of directly binding to the Rev and Rex response elements and functionally substituting for Rev and Rex functions [4 14 HSV-1 virions have four morphologically separate structures a DNA core capsid tegument and envelope. Tegument proteins fill the space between the capsid and the envelope [16]. US11 is a tegument protein and approximately 600 to 1 1 0 molecules per virion are released in the target cell upon virus entry [17]. It is a multifunctional protein involved in posttranscriptional regulation of gene expression and in biological processes related to the survival of cells following environmental stress [18 19 US11 is localized in the nucleus and the cytoplasm but especially accumulates in the nucleolus [20 21 It has been reported that US11 has RNA-binding activity and can associate strongly with ribosomes and has also been found in rRNA and polysome containing fractions [17 22 US11 also interacts with several host proteins including nucleolin [23] ubiquitous kinesin heavy chain (uKHC) [24] homeodomain-interacting protein kinases 2 (HIPK2) [19] and protein kinase R (PKR) [25] which in turn counteracts the antiviral host defense.