Competition model for upregulation of the major histocompatibility complex class II-associated invariant chain by human immunodeficiency virus type 1 Nef.
The human immunodeficiency virus type 1 (HIV-1) Nef protein upregulates the expression of the invariant chain (Ii)/major histocompatibility complex class II (MHC-II) complex at the cell surface. This complex appears to reach the antigen-loading endosomal compartment at least in part via an indirect pathway in which it is internalized from the cell surface via the adaptor protein 2 (AP-2) complex. Here we provide evidence for a competition model to explain how Nef upregulates the expression of Ii at the cell surface. In this model, Nef and Ii compete for binding to AP-2. In support of this model, Nef decreased the rate of internalization of Ii from the cell surface. The AP-binding dileucine motif in Nef, ENTSLL(165), was necessary and sufficient for the upregulation of Ii. In addition, two leucine-based AP-binding motifs in the Ii cytoplasmic tail, DDQRDLI(8) and EQLPML(17), were critical for the efficient upregulation of Ii by Nef. Experiments using Nef variants in which the native dileucine-based sorting motif was replaced with similar motifs from cellular transmembrane proteins allowed modulation of AP-binding specificity. Analysis of these variants suggested that the binding of Nef to AP-2 is sufficient to upregulate Ii at the plasma membrane. Finally, interference with the expression of AP-2 caused an upregulation of Ii at the plasma membrane, and this decreased the effect of Nef. These data indicate that Nef usurps AP-2 complexes to dysregulate Ii trafficking and potentially interfere with antigen presentation in the context of MHC-II.
Department of Medicine,1 Division of Biology, University of California, San Diego, La Jolla, CA 92093-0679, USA. rsmitchell@ucsd.edu
Richard S
RS
Mitchell
Rittik
R
Chaudhuri
O Wolf
OW
Lindwasser
Kristie A
KA
Tanaka
David
D
Lau
Rudy
R
Murillo
Juan S
JS
Bonifacino
John C
JC
Guatelli
D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D020816:Amino Acid Motifs; D017951:Antigen Presentation; D001667:Binding, Competitive; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D015693:Gene Products, nef / Q000096:biosynthesis* / Q000502:physiology*; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D007930:Leucine / Q000737:chemistry; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008954:Models, Biological
D033962:Adaptor Protein Complex 2; D015693:Gene Products, nef; D000949:Histocompatibility Antigens Class II; D007930:Leucine