Journal article
HIV-1 Nef Targets MHC-I and CD4 for Degradation Via a Final Common β-COP–Dependent Pathway in T Cells
PLoS pathogens, Vol.4(8), pp.e1000131-e1000131
08/01/2008
DOI: 10.1371/journal.ppat.1000131
PMCID: PMC2515349
PMID: 18725938
Abstract
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.
HIV is unique among viral pathogens in its capacity to cause chronic and
progressive disease in almost all infected people. To accomplish this, HIV must
evade the host immune response, especially cytotoxic T lymphocytes (CTLs), which
normally function to lyse virally infected cells. HIV encodes a factor, Nef,
which protects HIV infected cells from lysis by anti-HIV CTLs. To prevent CTL
lysis, Nef interferes with the expression of host MHC-I, which is needed for CTL
recognition of infected targets. A clear understanding of how Nef works has been
hampered by its many complex functions. In addition to MHC-I, Nef protein
disrupts the expression of multiple other cellular targets using different
mechanisms and it is unclear how one protein can accomplish all these tasks.
Here, we provide evidence that Nef acts as a highly flexible adaptor protein
that is capable of utilizing different protein binding domains depending on
which cellular target it is bound to. For example, we present evidence that Nef
binding to MHC-I creates novel motifs that result in the recruitment of AP-1 and
subsequently β-COP. This series of events results in the
mis-localization of MHC-I from the cell surface to cellular degradative
compartments, where MHC-I is destroyed.
Details
- Title: Subtitle
- HIV-1 Nef Targets MHC-I and CD4 for Degradation Via a Final Common β-COP–Dependent Pathway in T Cells
- Creators
- Malinda R. Schaefer - University of Michigan–Ann ArborElizabeth R. Wonderlich - University of Michigan–Ann ArborJeremiah F. Roeth - University of Michigan–Ann ArborJolie A. Leonard - University of Michigan–Ann ArborKathleen L. Collins - University of Michigan–Ann Arbor
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.4(8), pp.e1000131-e1000131
- Publisher
- Public Library of Science
- DOI
- 10.1371/journal.ppat.1000131
- PMID
- 18725938
- PMCID
- PMC2515349
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Alternative title
- Nef-Induced MHC-I and CD4 Degradation
- Language
- English
- Date published
- 08/01/2008
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9984696762502771
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