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

Mirna Perusina Lanfranca,David Davido,Heba Mostafa

doi:10.3390/cells3020438

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.

Highlights

Ubiquitination is an important regulator of protein function and stability within cells [1,2]
In this review we focus on the herpes simplex virus type 1 (HSV-1) E3 Ub ligase, infected cell protein 0 (ICP0), a RING-type E3 ligase that facilitates the transfer of Ub chains to a target substrate by acting as a scaffold that bridges the E2 enzyme and the target protein [19]
The role of nuclear domain 10 (ND10) in the function of ICP0 became apparent when it was shown that depletion of PML, Sp100, hDaxx, or ATRX could partially complement the replication of an ICP0-null mutant but had no effect on wild type HSV-1 [54]

Summary

Introduction

Ubiquitination is an important regulator of protein function and stability within cells [1,2]. ICP0’s ability to target constituents of both the intrinsic and innate branches of the immune system for proteasomal degradation through its E3 Ub ligase activity and the potential benefits or consequences for HSV-1 viral replication. Due to the presence of a RING-finger motif that mediates the interaction with E2 enzymes (Figure 1), ICP0 was hypothesized to have E3 Ub ligase activity This hypothesis was confirmed in a series of experiments that demonstrated ICP0’s ability to synthesize chains of poly-Ub in vitro and in cell culture [25,26,27,28,29]. As will be discussed below, the E3 Ub ligase activity of ICP0 plays a central role in HSV-1 replication by impairing components of the hosts’ intrinsic and innate antiviral responses

ICP0 Counteracts the Intrinsic Antiviral Resistance of ND10s and SUMO

MyD88 and Mal

NF-κB Signaling

Findings

Conclusions