13 research outputs found
HIV-1 Nef Targets MHC-I and CD4 for Degradation Via a Final Common β-COP–Dependent Pathway in T Cells
To facilitate viral infection and spread, HIV-1 Nef disrupts the surface
expression of the viral receptor (CD4) and molecules capable of presenting HIV
antigens to the immune system (MHC-I). To accomplish this, Nef binds to the
cytoplasmic tails of both molecules and then, by mechanisms that are not well
understood, disrupts the trafficking of each molecule in different ways.
Specifically, Nef promotes CD4 internalization after it has been transported to
the cell surface, whereas Nef uses the clathrin adaptor, AP-1, to disrupt normal
transport of MHC-I from the TGN to the cell surface. Despite these differences
in initial intracellular trafficking, we demonstrate that MHC-I and CD4 are
ultimately found in the same Rab7+ vesicles and are both
targeted for degradation via the activity of the Nef-interacting protein,
β-COP. Moreover, we demonstrate that Nef contains two separable
β-COP binding sites. One site, an arginine (RXR) motif in the N-terminal
α helical domain of Nef, is necessary for maximal MHC-I degradation. The
second site, composed of a di-acidic motif located in the C-terminal loop domain
of Nef, is needed for efficient CD4 degradation. The requirement for redundant
motifs with distinct roles supports a model in which Nef exists in multiple
conformational states that allow access to different motifs, depending upon
which cellular target is bound by Nef