Trends in Cell Biology
Nef—an adaptor adaptor?
Section snippets
CD4 endocytosis
CD4 endocytosis is normally regulated through two interconnected mechanisms (reviewed in Ref. [10]). In T cells, CD4 is associated with the Src-family tyrosine kinase p56Lck (Lck). Lck normally prevents CD4 endocytosis, and the CD4–Lck complex is restricted to the cell surface. Following activation of cells by antigen, receptor crosslinking or treatment with phorbol esters, the 38-amino-acid cytoplasmic domain of CD4 is phosphorylated on three conserved serine residues. Phosphorylation of
Nef-induced CD4 endocytosis
How, then, does Nef induce CD4 internalization? Nef effects on CD4 are independent of other viral proteins and occur in both Lck-positive and Lck-negative cells. CD4 phosphorylation is not required, although leucines 413 and 414 are essential11, 12. A direct interaction between Nef and CD4 has been difficult to detect since the two proteins cannot generally be coimmunoprecipitated from cell lysates. Nevertheless, an interaction has been seen when CD4 and Nef are expressed together in insect
What about Lck?
If Lck normally prevents CD4 endocytosis, how does Nef downmodulate CD4 in T cells? Lck and Nef appear to bind to overlapping regions of the CD4 cytoplasmic domain[1]. However, Lck can be coprecipitated with CD4, suggesting that it has a higher affinity for CD4 than Nef. Indeed, overexpression of Lck can inhibit Nef-induced CD4 downmodulation[22]. Nevertheless, under normal conditions, Nef enhances dissociation of the CD4–Lck complex[23]. Nef might simply compete with Lck for CD4 binding.
Other effects of Nef on CD4 trafficking
Studies with CD4–Nef and CD8–Nef chimeras suggest that CD4 transport through the Golgi apparatus is modified by Nef[7]. Nef–GFP chimeras also show some localization to the Golgi region in transfected cells15, 36, and HIV-2/SIV Nef proteins show weak interactions with Golgi-associated μ1 chains[17]. Thus Nef might also direct newly synthesized CD4 from the trans-Golgi network to endosomal compartments. Whether CD4 sorted by this route reaches the cell surface is unclear.
In Lck-negative cells,
And MHC I?
As with CD4, no direct interaction of Nef with MHC I has been reported. The modulation of MHC I is restricted to certain alleles; HLA-A and HLA-B are both downmodulated by Nef, but HLA-C is not[18]. Mutational analysis of the cytoplasmic domain of HLA-A2 and -B7 has indicated that Tyr320 is required for Nef downmodulation18, 36. This tyrosine is conserved in HLA-A and HLA-B alleles but is absent from HLA-C. Thus, Nef might be able to interact with the cytoplasmic domain of MHC I heavy chains
Concluding remarks
Many viruses can modulate the expression of specific host cell membrane proteins by interfering with the mechanisms that control the cellular distribution of these proteins. The ability of the adenovirus E3-19k protein to retain MHC I in the ER is well established[32]. Recent work with cytomegalovirus has illustrated other canny ways in which viruses inhibit MHC-I-mediated antigen presentation[32]. In addition to modulating protein traffic through the ER, viruses can interact with proteins that
Acknowledgements
We apologize to authors whose work we have not cited owing to space restrictions. We thank P. J. Klasse and Marie-José Bijlmakers for critical comments. The authors are supported by grants from the UK Medical Research Council.
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