Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters

Stable Identifier
R-HSA-164938
Type
Pathway
Species
Homo sapiens
Related Species
Human immunodeficiency virus 1
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The maximal virulence of HIV-1 requires Nef, a virally encoded peripheral membrane protein. Nef binds to the adaptor protein (AP) complexes of coated vesicles, inducing an expansion of the endosomal compartment and altering the surface expression of cellular proteins including CD4 and class I major histocompatibility complex.
Nef affects the cell surface expression of several cellular proteins. It down-regulates CD4, CD8, CD28, and major histocompatibility complex class I and class II proteins, but upregulates the invariant chain of MHC II (CD74). To modulate cell surface receptor expression, Nef utilizes several strategies, linked to distinct regions within the Nef protein.
Since all these receptors are essential for proper functions of the immune system, modulation of their surface expression by Nef has profound effects on anti-HIV immune responses. Down-regulation of MHC I protects HIV-infected cells from host CTL response, whereas down-modulation of CD28 and CD4 probably limits the adhesion of a Nef-expressing T cell to the antigen-presenting cell, thus promoting the movement of HIV-infected cells into circulation and the spread of the virus.

Literature References
PubMed ID Title Journal Year
9384576 Co-localization of HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nef-induced CD4 down-regulation

Greenberg, ME, Bronson, S, Lock, M, Neumann, M, Pavlakis, GN, Skowronski, J

EMBO J 1997
11208076 Two independent regions of HIV-1 Nef are required for connection with the endocytic pathway through binding to the mu 1 chain of AP1 complex

Erdtmann, L, Janvier, K, Raposo, G, Craig, HM, Benaroch, P, Berlioz-Torrent, C, Guatelli, JC, Benarous, R, Benichou, S

Traffic 2000
9736718 Interaction of HIV-1 Nef with the cellular dileucine-based sorting pathway is required for CD4 down-regulation and optimal viral infectivity

Craig, HM, Pandori, MW, Guatelli, JC

Proc Natl Acad Sci U S A 1998
9811606 A dileucine motif in HIV-1 Nef acts as an internalization signal for CD4 downregulation and binds the AP-1 clathrin adaptor

Bresnahan, PA, Yonemoto, W, Ferrell, S, Williams-Herman, D, Geleziunas, R, Greene, WC

Curr Biol 1998
9811611 A dileucine motif in HIV-1 Nef is essential for sorting into clathrin-coated pits and for downregulation of CD4

Greenberg, M, DeTulleo, L, Rapoport, I, Skowronski, J, Kirchhausen, T

Curr Biol 1998
12486136 HIV-1 Nef stabilizes the association of adaptor protein complexes with membranes

Janvier, K, Craig, H, Hitchin, D, Madrid, R, Sol-Foulon, N, Renault, L, Cherfils, J, Cassel, D, Benichou, S, Guatelli, J

J Biol Chem 2003
9586638 Nef interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC I molecules

Le Gall, S, Erdtmann, L, Benichou, S, Berlioz-Torrent, C, Liu, L, Benarous, R, Heard, JM, Schwartz, O

Immunity 1998
9564030 Mechanism of Nef-induced CD4 endocytosis: Nef connects CD4 with the mu chain of adaptor complexes

Piguet, V, Chen, YL, Mangasarian, A, Foti, M, Carpentier, JL, Trono, D

EMBO J 1998
Participants
Participant Of
Event Information
Disease
Name Identifier Synonyms
Human immunodeficiency virus infectious disease 526 HIV infection
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