title: Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression.
abstract: Herpes simplex virus 1 (HSV-1) causes one of the most prevalent herpesviral infections in humans and is the leading etiological agent of viral encephalitis and eye infections. Our understanding of how HSV-1 interacts with the host at the cellular and organismal levels is still limited. We and others previously reported that, upon infection, HSV-1 rapidly and efficiently downregulates CD1d cell surface expression and suppresses the function of NKT cells, a group of innate T cells with critical immunoregulatory function. The viral protein kinase US3 plays a major role in this immune evasion mechanism, and its kinase activity is required for this function. In this study, we investigated the cellular substrate(s) phosphorylated by US3 and how it mediates US3 suppression of CD1d recycling. We identified the type II kinesin motor protein KIF3A as a critical kinesin factor in the cell surface expression of CD1d. Interestingly, KIF3A is phosphorylated by US3 both in vitro and in infected cells. Mass spectrometry analysis of purified KIF3A showed that it is phosphorylated predominantly at serine 687 by US3. Ablation of this phosphorylation abolished US3-mediated downregulation of CD1d expression, suggesting that phosphorylation of KIF3A is the primary mechanism of HSV-1 suppression of CD1d expression by US3 protein. Understanding of the precise mechanism of viral modulation of CD1d expression will help to develop more efficient vaccines in the future to boost host NKT cell-mediated immune responses against herpesviruses.
  
  
  OBJECTIVE
  Herpes simplex virus 1 (HSV-1) is among the most common human pathogens. Little is known regarding the exact mechanism by which this virus evades the human immune system, particularly the innate immune system. We previously reported that HSV-1 employs its protein kinase US3 to modulate the expression of the key antigen-presenting molecule CD1d to evade the antiviral function of NKT cells. Here we identified the key cellular motor protein KIF3A as a cellular substrate phosphorylated by US3, and this phosphorylation event mediates US3-induced immune evasion.
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors: Ran
authors: R
authors: Xiong
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors: Ping
authors: P
authors: Rao
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors: Seil
authors: S
authors: Kim
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors: Michelle
authors: M
authors: Li
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors: Xiangshu
authors: X
authors: Wen
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA weiming.yuan@usc.edu.
authors: Weiming
authors: W
authors: Yuan
mesh_terms: D055610:Antigens, CD1d / Q000096:biosynthesis*; D015536:Down-Regulation; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology; D016547:Kinesins / Q000378:metabolism*; D013058:Mass Spectrometry; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D055610:Antigens, CD1d; C526877:CD1D protein, human; C087415:KIF3A protein, human; D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1; D016547:Kinesins