Infected cell protein 0 functional domains and their coordination in herpes simplex virus replication

Abstract

Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen that establishes latent infection in ganglia neurons. Its unique life cycle requires a balanced "conquer and compromise" strategy to deal with the host anti-viral defenses. One of HSV-1 α (immediate early) gene products, infected cell protein 0 (ICP0), is a multifunctional protein that interacts with and modulates a wide range of cellular defensive pathways. These pathways may locate in different cell compartments, which then migrate or exchange factors upon stimulation, for the purpose of a concerted and effective defense. ICP0 is able to simultaneously attack multiple host pathways by either degrading key restrictive factors or modifying repressive complexes. This is a viral protein that contains an E3 ubiquitin ligase, translocates among different cell compartments and interacts with major defensive complexes. The multiple functional domains of ICP0 can work independently and at the same time coordinate with each other. Dissecting the functional domains of ICP0 and delineating the coordination of these domains will help us understand HSV-1 pathogenicity as well as host defense mechanisms. This article focuses on describing individual ICP0 domains, their biochemical properties and their implication in HSV-1 infection. By putting individual domain functions back into the picture of host anti-viral defense network, this review seeks to elaborate the complex interactions between HSV-1 and its host.

Keywords: Chromatin repression; E3 ubiquitin ligase; Herpes simplex virus 1; Infected cell protein 0; ND10 nuclear bodies; Protein modification; Subcellular translocation.

Figure 1

Schematic diagram of infected cell protein 0 gene structure and functional domains. Line 1: Genome structure of HSV-1; Line 2: Locations of the two inverted copies of ICP0 gene in the HSV-1 genome; Line 3: ICP0 gene structure and domain properties. The amino acid numbers are labeled above the illustration of ICP0 gene. RING finger domain, Proline-rich ND10-FSs and nuclear localization signal are represented by a green oval with “R”, brown squares with “FS” and a blue rectangle with “NLS”, respectively. The binding sites for RNF8 (T67), Cyclin D3 (D199), USP7 (K620/K624), and CoREST (D671/E673) are represented by the dark blue boxes above or beneath the ICP0 gene. The positions of the seven SLSs are represented by lavender hexagons with “S” in the center. The positions of the three phosphorylation clusters are represented by dark green circles with “P” in the center. ICP0: Infected cell protein 0; HSV-1: Herpes simplex virus 1; RING: Really interesting new gene; ND10: Nuclear domains 10; NLS: Nuclear localization signal; USP7: Ubiquitin-specific protease 7; SLSs: SIM-like sequences.