Abstract
Herpesvirus saimiri Tip associates with Lck and downregulates Lck signal transduction. Here we demonstrate that Tip targets a lysosomal protein p80, which consists of an N-terminal WD repeat domain and a C-terminal coiled-coil domain. Interaction of Tip with p80 facilitated lysosomal vesicle formation and subsequent recruitment of Lck into the lysosomes for degradation. Consequently, Tip interactions with Lck and p80 result in downregulation of T cell receptor (TCR) and CD4 surface expression. Remarkably, these actions of Tip are functionally and genetically separable: the N-terminal p80 interaction is responsible for TCR downregulation and the C-terminal Lck interaction is responsible for CD4 downregulation. Thus, lymphotropic herpesvirus has evolved an elaborate mechanism to deregulate lymphocyte receptor expression to disarm host immune control.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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CD4 Antigens / metabolism
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COS Cells
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Cell Line, Transformed
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Chlorocebus aethiops
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DNA, Complementary
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Down-Regulation*
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Endosomes / metabolism
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Gene Expression
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Humans
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Intracellular Signaling Peptides and Proteins
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Jurkat Cells
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism*
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Lysosomes / metabolism
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Molecular Sequence Data
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Phosphoproteins / metabolism*
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Protein Structure, Tertiary
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Proteins / genetics
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Proteins / metabolism*
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Receptors, Antigen, T-Cell / metabolism*
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Sequence Homology, Amino Acid
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Viral Proteins / metabolism*
Substances
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CD4 Antigens
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DNA, Complementary
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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Proteins
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Receptors, Antigen, T-Cell
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Viral Proteins
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WDR48 protein, human
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tyrosine kinase interacting protein, Saimiriine herpesvirus 2
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)