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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2012)

Natural killer (NK) cells are lymphocytes that play a major role in the elimination of virally-infected cells and tumor cells. NK cells recognize and target abnormal cells through activation of stimulatory receptors such as NKG2D. NKG2D ligands are self-proteins, which are absent or expressed at low levels on healthy cells but are induced upon cellular stress, transformation, or viral infection. The exact molecular mechanisms driving expression of these ligands remain poorly understood.

Using mouse cytomegalovirus (MCMV) as a model, the present dissertation describes three distinct factors that contribute to the induction of the RAE-1 family of NKG2D ligands during MCMV infection. First, we show that activation of the phosphatidylinositol-3-kinase (PI3K) pathway, which is often dysregulated during infection and tumorigenesis, is required for RAE-1 expression in MCMV-infected cells as well as in transformed cell lines. Second, genetic manipulation of the MCMV genome has revealed a novel viral protein encoded by the m18 gene that is both necessary and sufficient to induce RAE-1 expression. Finally, studies using mouse strains that are deficient in various innate signaling molecules demonstrate that innate signaling through the MyD88 adaptor protein and the IRF3 transcription factor are involved in RAE-1 induction.

Collectively, we have shown that RAE-1 expression during MCMV infection involves a combination of signals to ensure that its expression is limited to truly diseased cells.

    Cover page: Understanding the Mechanism of Stimulatory NK-cell Ligand Expression
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2011)
    Natural killer (NK) cells are lymphocytes that play a major role in the elimination of virally-infected cells and tumor cells. NK cells recognize and target abnormal cells through activation of stimulatory receptors such as NKG2D. NKG2D ligands are self-proteins, which are absent or expressed at low levels on healthy cells but are induced upon cellular stress, transformation, or viral infection. The exact molecular mechanisms driving expression of these ligands remain poorly understood. Here we show that murine cytomegalovirus (MCMV) infection activates the phosphatidylinositol-3-kinase (PI3K) pathway and that this activation is required for the induction of the RAE-1 family of mouse NKG2D ligands. Among the multiple PI3K catalytic subunits, inhibition of the p110α catalytic subunit blocks this induction. Similarly, inhibition of p110α PI3K reduces cell surface expression of RAE-1 on transformed cells. Many viruses manipulate the PI3K pathway, and tumors frequently mutate the p110α oncogene. Thus, our findings suggest that dysregulation of the PI3K pathway is an important signal to induce expression of RAE-1, and this may represent a commonality among various types of cellular stresses that result in the induction of NKG2D ligands.
      Cover page: Expression of the RAE-1 Family of Stimulatory NK-Cell Ligands Requires Activation of the PI3K Pathway during Viral Infection and Transformation
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2008)
      MHC class I molecules present a comprehensive mixture of peptides on the cell surface for immune surveillance. The peptides represent the intracellular protein milieu produced by translation of endogenous mRNAs. Unexpectedly, the peptides are encoded not only in conventional AUG initiated translational reading frames but also in alternative cryptic reading frames. Here, we analyzed how ribosomes recognize and use cryptic initiation codons in the mRNA. We find that translation initiation complexes assemble at non-AUG codons but differ from canonical AUG initiation in response to specific inhibitors acting within the peptidyl transferase and decoding centers of the ribosome. Thus, cryptic translation at non-AUG start codons can utilize a distinct initiation mechanism which could be differentially regulated to provide peptides for immune surveillance.
        Cover page: A Distinct Translation Initiation Mechanism Generates Cryptic Peptides for Immune Surveillance
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2016)
        Natural Killer (NK) cells are essential for control of viral infection and cancer. NK cells express NKG2D, an activating receptor that directly recognizes NKG2D ligands. These are expressed at low level on healthy cells, but are induced by stresses like infection and transformation. The physiological events that drive NKG2D ligand expression during infection are still poorly understood. We observed that the mouse cytomegalovirus encoded protein m18 is necessary and sufficient to drive expression of the RAE-1 family of NKG2D ligands. We demonstrate that RAE-1 is transcriptionally repressed by histone deacetylase inhibitor 3 (HDAC3) in healthy cells, and m18 relieves this repression by directly interacting with Casein Kinase II and preventing it from activating HDAC3. Accordingly, we found that HDAC inhibiting proteins from human herpesviruses induce human NKG2D ligand ULBP-1. Thus our findings indicate that virally mediated HDAC inhibition can act as a signal for the host to activate NK-cell recognition.
          Cover page: A Herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repression.Creative Commons 'BY-NC-ND' version 4.0 license
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