Herpesviral Protein Targets a Cellular WD Repeat Endosomal Protein to Downregulate T Lymphocyte Receptor Expression

Park, Junsoo; Lee, Bok Soo; Choi, Joong Kook; Means, Robert E.; Choe, Joonho; Jung, Jae U.

doi:10.1016/s1074-7613(02)00368-0

Cited by 54 publications

(86 citation statements)

References 29 publications

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“…Likewise, HIV-infected T cells had reduced ability to from synapses with APCs. In T cells infected with HSV, Lck was targeted to lysosomes, where it underwent degradation (34). As a result, the amount of Lck at the plasma membrane was substantially reduced.…”

Section: Discussionmentioning

confidence: 99%

Uncoordinated 119 Protein Controls Trafficking of Lck via the Rab11 Endosome and Is Critical for Immunological Synapse Formation

Górska

Qiang

Karim

et al. 2009

The Journal of Immunology

108

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The activation of T cells through the TCR is essential for development of the adaptive immune response. TCR does not have any enzymatic activity and relies on the plasma membrane-associated lymphocyte-specific protein tyrosine kinase (Lck) for initiation of signaling. Here we uncover a mechanism that is responsible for plasma membrane targeting of Lck. We show that Lck is transported to the membrane via a specific endosomal compartment. The transport depends on the adaptor protein Uncoordinated 119 (Unc119), on the GTPase rat brain 11 (Rab11), and on the actin cytoskeleton. Unc119 regulates the activation of Rab11. Consequently, Unc119 orchestrates the recruitment of the actin-based motor protein, myosin 5B, and the organization of multiprotein complexes on endosomes. The Unc119-regulated pathway is essential for immunological synapse formation and T cell activation.

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Section: Discussionmentioning

confidence: 99%

Uncoordinated 119 Protein Controls Trafficking of Lck via the Rab11 Endosome and Is Critical for Immunological Synapse Formation

Górska

Qiang

Karim

et al. 2009

The Journal of Immunology

108

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“…Like T cells transformed with the parental HVS C488 (28), they displayed typical surface markers of mature T cells. It has been reported that overexpression of Tip in T-cell lines results in a downmodulation of CD3 and CD4 surface expression (57), which was more pronounced in Tip-Y114S (32,58). In our hands, HVS-transformed cells expressing the HVS oncogene tip from the viral promoter do not show such a dramatic effect; instead, they showed only a modestly lower surface expression of CD3 in C488-Y114F-transformed cells compared to HVS-C488-transformed cells and normal expression of CD4 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…STAT3 would have been an attractive candidate, but it is excluded by this study. Numerous other proteins not yet characterized have been reported to bind Tip (58,66). Of these proteins, there may be interesting candidates interfering with cellular signaling pathways contributing to transformation.…”

Section: Discussionmentioning

confidence: 99%

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

Heck

Lengenfelder

Schmidt

et al. 2005

J Virol

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Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that were originally discovered as key mediators of cytokine signaling. They are involved in signaling by the interleukin-6 (IL-6) family cytokines, the IL-2 family cytokines, and numerous growth factors, including epidermal growth factor, platelet-derived growth factor, and colony-stimulating factor 1. Latent inactive STATs reside in the cytoplasm; in response to receptor activation, they are recruited to a receptor where they are tyrosine phosphorylated by receptor tyrosine kinases (RTK) or receptor-associated tyrosine kinases, such as JAK or Trk kinases (reviewed in references 36, 42, 46, and 48). Active STAT dimers are then formed via the reciprocal interaction between the SH2 domain of one monomer and the phosphorylated tyrosine of the other. Activated dimers translocate to the nucleus, where they bind to specific DNA response elements in the promoters of target genes and activate transcription. Furthermore, various oncoproteins can activate specific STAT molecules (especially STAT3 and STAT5) (8,15), and inappropriate STAT activation directly contributes to oncogenesis by stimulating cell proliferation and preventing apoptosis. Constitutive activation of several STATs was frequently detected in a wide range of human cell lines and primary tumors, including lymphoid malignancies (lymphomas, leukemias, and multiple myelomas) (30,63,67). Constitutively activated mutant STAT3 and STAT5 proteins have been shown to possess transforming properties and to be strongly associated with tumor development and progression (7, 9).

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“…ORF14 protein, a homolog of MMTV vSag, is detected primarily during lytic replication and induces the polyclonal proliferation of CD4-positive T cells through an interaction with MHC class II-TCR molecules (60). Tip, which is expressed primarily during viral latency, interacts with Lck tyrosine kinase and p80 endosomal protein and thus interferes with early events in the TCR signal transduction pathway and induces a rapid endocytosis of the TCR complex (39,40). Finally, ORF5, which is expressed primarily during viral replication cycle but not during the viral latent cycle (unpublished results), interacts with cellular SH2-containing proteins, which results in the strong augmentation of TCR signal transduction.…”

Section: Discussionmentioning

confidence: 97%

“…As a lipid raft resident protein, Tip interacts with the SH3 domain of Lck tyrosine kinase, and this interaction interferes with early events in the TCR signal transduction pathway (3,27,35). Furthermore, Tip interacts with a novel cellular endosomal protein, p80, which contains an amino-terminal WD repeat domain and a carboxy-terminal coiled-coil domain (39,40). Interaction of Tip with p80 facilitates endosomal vesicle formation and subsequent recruitment of Lck and TCR into the endosomes for degradation.…”

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confidence: 99%

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Lee

Chung

Cho

et al. 2004

Molecular and Cellular Biology

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Because of its central regulatory role, T-cell receptor (TCR) signal transduction is a common target of viruses. We report here the identification of a small signaling protein, ORF5, of the T-lymphotropic tumor virus herpesvirus saimiri (HVS). ORF5 is predicted to contain 89 to 91 amino acids with an amino-terminal myristoylation site and six SH2 binding motifs, showing structural similarity to cellular LAT (linker for activation of T cells). Sequence analysis showed that, despite extensive sequence variation, the myristoylation site and SH2 binding motifs were completely conserved among 13 different ORF5 isolates. Upon TCR stimulation, ORF5 was efficiently tyrosine phosphorylated and subsequently interacted with cellular SH2-containing signaling proteins Lck, Fyn, SLP-76, and p85 through its tyrosine residues. ORF5 expression resulted in the marked augmentation of TCR signal transduction activity, evidenced by increased cellular tyrosine phosphorylation, intracellular calcium mobilization, CD69 surface expression, interleukin-2 production, and activation of the NF-AT, NF-B, and AP-1 transcription factors. Despite its structural similarity to cellular LAT, however, ORF5 could only partially substitute for LAT function in TCR signal transduction. These results demonstrate that HVS utilizes a novel signaling protein, ORF5, to activate TCR signal transduction. This activation probably facilitates viral gene expression and, thereby, persistent infection.Upon engagement of the T-cell antigen receptor (TCR), many cellular proteins, including TCR subunits, adaptor proteins, and other effector molecules, are phosphorylated and subsequently are involved in the formation of molecular complexes at the site of contact with the antigen-presenting cells (33, 51, 54) The earliest signaling event following TCR engagement is the sequential activation of the non-receptor protein tyrosine kinases (PTKs) of the Src and Syk families. Activated Src family PTKs, Lck and Fyn, in T cells subsequently phosphorylate tyrosine residues within a consensus sequence termed the immunoreceptor tyrosine-based activation motif in the cytosolic tails of the TCR subunits. The phosphorylated immunoreceptor tyrosine-based activation motifs of TCR in turn recruit the Syk family PTKs ZAP70 and Syk through their Src homology 2 (SH2) domains (33). Together with Lck and Fyn, the ZAP70 and Syk kinases then promote the phosphorylation of many intracellular signaling molecules, including phospholipase C-␥1 (PLC-␥1), Cbl, Vav, LAT (linker for activation of T cells) and SLP-76 (SH2-containing leukocyte protein-76) (12,25,41,45,46,53). Phosphorylation of these cellular signaling molecules ultimately induces various cellular events such as cytoskeletal alteration, intracellular Ca ϩϩ influx, transcription factor activation, and cytokine/chemokine production (4,20,38,43,59).Two adaptor proteins, LAT and SLP-76, have been shown to be critical for the optimal activation of T cells and to function in linking proximal signaling events to distal downstream signaling ac...

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Herpesviral Protein Targets a Cellular WD Repeat Endosomal Protein to Downregulate T Lymphocyte Receptor Expression

Cited by 54 publications

References 29 publications

Uncoordinated 119 Protein Controls Trafficking of Lck via the Rab11 Endosome and Is Critical for Immunological Synapse Formation

Uncoordinated 119 Protein Controls Trafficking of Lck via the Rab11 Endosome and Is Critical for Immunological Synapse Formation

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

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