Effects of Phosphorylation of Herpes Simplex Virus 1 Envelope Glycoprotein B by Us3 Kinase In Vivo and In Vitro

Herpes simplex viruses (HSVs) are prevalent human pathogens that establish latency in human neuronal cells and efficiently evade the immune system. It has been a major medical challenge to eradicate them and, despite intensive efforts, an effective vaccine is not available. We previously showed that upon infection of antigen-presenting cells, HSV type 1 (HSV-1) rapidly and efficiently downregulates the major histocompatibility complex class I-like antigen-presenting molecule, CD1d, and potently inhibits its recognition by CD1d-restricted natural killer T (NKT) cells. It suppresses CD1d expression primarily by inhibiting its recycling to the cell surface after endocytosis. We identify here the viral glycoprotein B (gB) as the predominant CD1d-interacting protein. gB initiates the interaction with CD1d in the endoplasmic reticulum and stably associates with it throughout CD1d trafficking. However, an additional HSV-1 component, the serine-threonine kinase US3, is required for optimal CD1d downregulation. US3 expression in infected cells leads to gB enrichment in the trans-Golgi network (TGN) and enhances the relocalization of both gB and CD1d to this compartment, suggesting that following internalization CD1d is translocated from the endocytic pathway to the TGN by its association with gB. Importantly, both US3 and gB are required for efficient inhibition of CD1d antigen presentation and NKT cell activation. In summary, our results suggest that HSV-1 uses gB and US3 to rapidly inhibit NKT cell function in the initial antiviral response.

Section: Resultsmentioning

confidence: 99%

Section: Vol 85 2011mentioning

confidence: 99%

Herpes Simplex Virus 1 Glycoprotein B and US3 Collaborate To Inhibit CD1d Antigen Presentation and NKT Cell Function

Rao

Pham

Kulkarni

et al. 2011

“…In experimental animal models of HSV-1 infection, viral pathogenesis in sites peripheral to the initial infection site (pathogenic manifestations in peripheries) and destruction of the central nervous system caused by viral replication (neurovirulence) are semi-independent indicators of viral virulence and can be studied by peripheral and intracerebral inoculation, respectively (26,29). To our knowledge, a viral protein that is involved in neurovirulence in mice is, in most cases, required for viral pathogenic manifestations in peripheries as well, whereas a viral protein that is involved in pathogenic manifestations in peripheries in mice often has no effect on viral neurovirulence.…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus 1 VP22 Regulates Translocation of Multiple Viral and Cellular Proteins and Promotes Neurovirulence

Tanaka

Kato

Satoh

et al. 2012

Self Cite

Herpes simplex virus 1 (HSV-1) protein VP22, encoded by the UL49 gene, is a major virion tegument protein. In the present study, we showed that VP22 was required for efficient redistribution of viral proteins VP16, VP26, ICP0, ICP4, and ICP27 and of cellular protein Hsc-70 to the cytoplasm of infected cells. We found that two dileucine motifs in VP22, at amino acids 235 and 236 and amino acids 251 and 252, were necessary for VP22 regulation of the proper cytoplasmic localization of these viral and cellular proteins. The dileucine motifs were also required for proper cytoplasmic localization of VP22 itself and for optimal expression of viral proteins VP16, VP22, ICP0, UL41, and glycoprotein B. Interestingly, a recombinant mutant virus with alanines substituted for the dileucines at amino acids 251 and 252 had a 50% lethal dose (LD 50 ) for neurovirulence in mice following intracerebral inoculation about 10 3 -fold lower than the LD 50 of the repaired virus. Furthermore, the replication and spread of this mutant virus in the brains of mice following intracerebral inoculation were significantly impaired relative to those of the repaired virus. The ability of VP22 to regulate the localization and expression of various viral and cellular proteins, as shown in this study, was correlated with an increase in viral replication and neurovirulence in the experimental murine model. Thus, HSV-1 VP22 is a significant neurovirulence factor in vivo. Herpes simplex virus 1 (HSV-1) virions, like those of other herpesviruses, consist of three morphologically distinct structures: the nucleocapsid, containing the linear doublestranded DNA viral genome, which encodes at least 84 viral proteins, in an icosahedral capsid; the tegument, a proteinaceous layer surrounding the nucleocapsid; and the envelope, a host cellderived lipid bilayer with viral glycoproteins enclosing the nucleocapsid and tegument (55). The tegument consists of a large number of proteins, including at least 26 viral proteins (41). Tegument proteins are released into the cytoplasm upon the fusion of the virion envelope with the host cell membrane and therefore may function to establish an environment for effective initiation of very early infection. However, the roles of only a few tegument proteins, including the immediate-early gene transactivator VP16, encoded by the UL48 gene, and the virion host shutoff protein VHS, encoded by the UL41 gene (55), in very early infection have been established. Large amounts of newly synthesized tegument proteins have also been shown to modulate the host cellular environment and to regulate various viral replication processes later in infection (28).VP22, encoded by the UL49 gene, is one of the major HSV-1 tegument proteins, and its amino acid sequence is conserved in the subfamily Alphaherpesvirinae. It appears that the functional requirements of VP22 homologues in the viral life cycle differ among alphaherpesviruses. For example, the VP22 homologues of Marek's disease virus serotype 1 and varicella-zoster virus are considered to...

“…HSV-1 US3 phosphorylates the cytoplasmic domain of the envelope glycoprotein gB (83). The gB protein is one of the viral proteins that is essential to mediate fusion between envelope and host membrane during viral entry.…”

Section: Herpesvirusesmentioning

confidence: 99%

Viral Serine/Threonine Protein Kinases

Jacob

Broeke

Favoreel

2011

109

Phosphorylation represents one the most abundant and important posttranslational modifications of proteins, including viral proteins. Virus-encoded serine/threonine protein kinases appear to be a feature that is unique to large DNA viruses. Although the importance of these kinases for virus replication in cell culture is variable, they invariably play important roles in virus virulence. The current review provides an overview of the different viral serine/threonine protein kinases of several large DNA viruses and discusses their function, importance, and potential as antiviral drug targets.