Abstract
Immediate-early protein ICP0 of herpes simplex virus type 1 (HSV-1) is important for the regulation of lytic and latent viral infection. Like the related proteins expressed by other alphaherpesviruses, ICP0 has a zinc-stabilized RING finger domain that confers E3 ubiquitin ligase activity. This domain is essential for the core functions of ICP0 and its activity leads to the degradation of a number of cellular proteins, some of which are involved in cellular defences that restrict viral infection. The article reviews recent advances in ICP0-related research, with an emphasis on the mechanisms by which ICP0 and related proteins counteract antiviral restriction and the roles in this process of cellular nuclear substructures known as ND10 or PML nuclear bodies. We also summarize recent advances in the understanding of the biochemical aspects of ICP0 activity. These studies highlight the importance of the SUMO conjugation pathway in both intrinsic resistance to HSV-1 infection and in substrate targeting by ICP0. The topics discussed in this review are relevant not only to HSV-1 infection, but also to cellular intrinsic resistance against herpesviruses more generally and the mechanisms by which viruses can evade this restriction.
Highlights
After a primary infection, herpesviruses establish life-long latent infections that periodically reactivate to enable transmission between individuals and ensure viral maintenance within the host population (Knipe et al, 2006)
Studies over the past three decades have shown that ICP0 directly influences, and in some cases inhibits, many fundamental cellular processes, including DNA repair, transcription, the cell cycle, and innate and intrinsic antiviral immunity
As the number of pathways known to be influenced by ICP0 grows, it has become increasingly important to understand their relative contributions to the regulation of lytic infection and viral reactivation
Summary
Herpesviruses establish life-long latent infections that periodically reactivate to enable transmission between individuals and ensure viral maintenance within the host population (Knipe et al, 2006). All alphaherpesviruses that infect mammalian species express a member of the ICP0 family of proteins, which is defined by the presence of domain, known as a RING finger, that coordinates two zinc atoms by conserved cysteine and histidine residues (Fig. 1; Barlow et al, 1994) This domain confers E3 ubiquitin ligase activity to ICP0 and its viral orthologues (Boutell et al, 2002; Everett et al, 2010; Hagglund et al, 2002), mediating the ubiquitination and proteasome-dependent degradation of several cellular proteins during infection (Table 1). Experiments that investigate consequences to the cell should be done at high multiplicity to ensure that all the cells are actively infected This concept is based on the distinction between the direct effects of ICP0 itself, and the indirect effects resulting from a failure to commit to lytic infection and defects in the expression of other viral proteins.
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