HSV-1 ICP0: An E3 Ubiquitin Ligase That Counteracts Host Intrinsic and Innate Immunity

Abstract

The herpes simplex virus type 1 (HSV-1) encoded E3 ubiquitin ligase, infected cell protein 0 (ICP0), is required for efficient lytic viral replication and regulates the switch between the lytic and latent states of HSV-1. As an E3 ubiquitin ligase, ICP0 directs the proteasomal degradation of several cellular targets, allowing the virus to counteract different cellular intrinsic and innate immune responses. In this review, we will focus on how ICP0's E3 ubiquitin ligase activity inactivates the host intrinsic defenses, such as nuclear domain 10 (ND10), SUMO, and the DNA damage response to HSV-1 infection. In addition, we will examine ICP0's capacity to impair the activation of interferon (innate) regulatory mediators that include IFI16 (IFN γ-inducible protein 16), MyD88 (myeloid differentiation factor 88), and Mal (MyD88 adaptor-like protein). We will also consider how ICP0 allows HSV-1 to evade activation of the NF-κB (nuclear factor kappa B) inflammatory signaling pathway. Finally, ICP0's paradoxical relationship with USP7 (ubiquitin specific protease 7) and its roles in intrinsic and innate immune responses to HSV-1 infection will be discussed.

Figure 1

Functional domains and sites in ICP0 relevant to this review. The T67 phosphorylation site, RING-finger motif, ICP0 phosphorylation (Phos) region I (amino acids 224–232), nuclear localization signal (NLS), USP7 binding site, ND10 localization domain, and SIMs (SUMO interaction motifs) 1–7, which start at amino acids 162, 174, 331, 360, 650, 665, and 679 of ICP0, respectively [22].

Figure 2

The HSV-1 ICP0 E3 ubiquitin ligase activity counteracts components of host intrinsic and innate immunity by targeting the degradation or dissociation of specific cellular proteins. Many ICP0 targets are multi-functional and participate in both intrinsic and innate antiviral responses and affect several processes, which includes (1) Viral transcription: PML, Sp100, and SUMO; (2) Viral genome silencing: IFI16; (3) Inflammatory mechanisms and NF-κB regulation: IFI16, MyD88, Mal, NF-κB, and IκB; (4) Viral replication: PARG; (5) DNA damage response: RNF168, RNF8, and DNA-PKcs; and (6) ICP0 destabilization, TLR signaling, Chromatinization, NF-κB signaling: USP7.