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/CD3 Complex, But Not CD28, Interact with Clathrin Adaptor Complexes AP-1 and AP-2
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Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115;
Sackler School of Biomedical Sciences, Tufts University, and
Center for Blood Research, and Departments of
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Medicine,
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Pathology, and
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Cell Biology, Harvard Medical School, Boston, MA 02115
The negative signaling receptor cytolytic T lymphocyte-associated
Ag-4 (CTLA-4) resides primarily in intracellular compartments such as
the Golgi apparatus of T cells. However, little is known regarding the
molecular mechanisms that influence this accumulation. In this study,
we demonstrate binding of the clathrin adaptor complex AP-1 with the
GVYVKM motif of the cytoplasmic domain of CTLA-4. Binding occurred
primarily in the Golgi compartment of T cells, unlike with AP-2 binding
that occurs mostly with cell surface CTLA-4. Although evidence was not
found to implicate AP-1 binding in the retention of CTLA-4 in the
Golgi, AP-1 appears to play a role in shuttling of excess receptor from
the Golgi to the lysosomal compartments for degradation. In support of
this, increased CTLA-4 synthesis resulted in an increase in CTLA-4/AP-1
binding and a concomitant increase in the appearance of CTLA-4 in the
lysosomal compartment. At the same time, the level of intracellular
receptor was maintained at a constant level, suggesting that
CTLA-4/AP-1 binding represents one mechanism to ensure steady state
levels of intracellular CTLA-4 in T cells. Finally, we demonstrate that
the TCR
/CD3 complex (but not CD28) also binds to AP-1 and AP-2
complexes, thus providing a possible link between these two receptors
in the regulation of T cell function.
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