Herpesviral protein targets a cellular WD repeat endosomal protein to downregulate T lymphocyte receptor expression.
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.
Department of Microbiology and Molecular Genetics, New England Regional Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
Junsoo
J
Park
Bok-Soo
BS
Lee
Joong-Kook
JK
Choi
Robert E
RE
Means
Joonho
J
Choe
Jae U
JU
Jung
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015704:CD4 Antigens / Q000378:metabolism; D019556:COS Cells; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D018076:DNA, Complementary; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014764:Viral Proteins / Q000378:metabolism*; D009687:Nuclear Proteins
D015704:CD4 Antigens; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D010750:Phosphoproteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; C092384:tyrosine kinase interacting protein, Saimiriine herpesvirus 2; C526165:WDR48 protein, human; D009687:Nuclear Proteins