Keep it in the subfamily: the conserved alphaherpesvirus US3 protein kinase

Abstract

The US3 protein kinase is conserved over the alphaherpesvirus subfamily. Increasing evidence shows that, although the kinase is generally not required for virus replication in cell culture, it plays a pivotal and in some cases an essential role in virus virulence in vivo. The US3 protein is a multifunctional serine/threonine kinase that is involved in viral gene expression, virion morphogenesis, remodelling the actin cytoskeleton and the evasion of several antiviral host responses. In the current review, both the well conserved and virus-specific functions of alphaherpesvirus US3 protein kinase orthologues will be discussed. IntroductionAlphaherpesviruses represent the largest subfamily of the herpesviruses. The natural hosts of alphaherpesviruses vary from birds to humans. Like other herpesviruses, alphaherpesviruses establish lifelong latent infections in their natural host. Reactivation from latency upon specific, often stress-and/or immune suppression-related stimuli, may lead to recurrent disease symptoms. Three alphaherpesviruses have been described in humans: herpes simplex virus type 1 (HSV-1), HSV-2 and varicella-zoster virus (VZV). HSV-1 and HSV-2 are primarily associated with cold sores and genital lesions, but may rarely also cause devastating disease symptoms, including keratitis, blindness and encephalitis. VZV is the causitive agent of chickenpox and shingles. A fourth alphaherpesvirus, herpes B virus, causes life threatening encephalitis in man, but its natural host is the macaque monkey. The alphaherpesviruses also comprise several important animal alphaherpesviruses. Pseudorabies virus (PRV) causes encephalitis, respiratory symptoms and abortions in swine. Bovine herpesvirus type 1 (BoHV-1) is the causative agent of infectious bovine rhinotracheitis in cattle and may also cause abortions. In horses, symptoms associated with equine herpesvirus type 1 (EHV-1) may vary from respiratory problems to paralysis and abortion. Marek's disease virus (MDV) causes lethal infections in chickens, and, quite atypical for alphaherpesviruses, is a cancercausing virus.The US3 protein kinase is encoded by every alphaherpesvirus identified thus far, indicating that it is vital for viral fitness, although it is often not required for growth of the virus in cell culture (Frame et al., 1987;Hanks et al., 1988;Heineman et al., 1996;McGeoch & Davison, 1986;Purves et al., 1987). The US3 designation refers to the position of the gene in the prototypical herpes simplex virus genome, where it constitutes the third gene in the unique short segment. For most alphaherpesviruses, US3 orthologues are also referred to as US3, except for VZV, where ORF66 represents the US3 orthologue.All alphaherpesvirus US3 orthologues have a kinase domain of 280-300 aa containing the ATP-binding domain and the catalytic active site (Fig. 1). The invariant lysine (K) in the former is critical for ATP binding and the invariant aspartic acid (D) in the latter is critical for catalytic activity. These critical invariant residues are often targets f...

Phosphorylation of a Herpes Simplex Virus 1 dUTPase by a Viral Protein Kinase, Us3, Dictates Viral Pathogenicity in the Central Nervous System but Not at the Periphery

“…HSV-1 Us3 has been considered to be a multifunctional protein regulating various aspects of cellular and viral functions (5). Supporting to this hypothesis, more than 15 putative viral and cellular substrates of Us3 have been reported (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

“…erpes simplex virus 1 (HSV-1) encodes at least two protein kinases, Us3 and UL13 (1)(2)(3)(4)(5)(6). HSV-1 Us3 is a serine/threonine protein kinase with an amino acid sequence that is conserved in the subfamily Alphaherpesvirinae (1,2).…”

Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a

“…Targeting of aminophospholipid exposure and signaling pathways, such as those mediated by group I PAKs, and identification of the viral factors that trigger these events may therefore hold promise as therapeutic strategies for viral diseases (76,77). The viral US3 protein kinase may be of particular interest in this respect, since it is an important alphaherpesvirus virulence factor, and since US3 does not appear to be closely related genetically to any known cellular kinase, which may make it an attractive candidate to target for the development of antiviral drugs (78).…”

Plus-end tracking proteins, CLASPs, and a viral Akt mimic regulate herpesvirus-induced stable microtubule formation and virus spread

“…infection in many cell lines, is important for efficient anterograde movement and HSV-1 spread in vivo and in specific cell types, notably including NHDFs (21,22,(31)(32)(33)(34). In terms of cytoskeletal regulation, a number of its properties potentially position Us3 as a central regulator of host MTs that may underlie differences with other viral strategies.…”