Mechanism for down-regulation of CD28 by Nef

Swigut, T., Shohdy, N., Skowronski, J. (April 2001) Mechanism for down-regulation of CD28 by Nef. Embo Journal, 20 (7). pp. 1593-1604. ISSN 0261-4189

URL: http://www.ncbi.nlm.nih.gov/pubmed/11285224
DOI: 10.1093/emboj/20.7.1593

Abstract

SIV and HIV Nef proteins disrupt T-cell receptor machinery by down-modulating cell surface expression of CD4 and expression or signaling of CD3-TCR. Nef also down-modulates class I major histocompatibility complex (MHC) surface expression. We show that SIV and HIV-1 Nefs down-modulate CD28, a major co-stimulatory receptor that mediates effective T-cell activation, by accelerating CD28 endocytosis, The effects of Nef on CD28, CD4, CD3 and class I MHC expression are all genetically separable, indicating that all are selected independently. In cells expressing a Nef-green fluorescent protein (GFP) fusion, CD28 co-localizes with the AP-2 clathrin adaptor and Nef-GFP. Mutations that disrupt Nef interaction with AP-2 disrupt CD28 down-regulation. Furthermore, HIV and SIV Nefs use overlapping but distinct target sites in the membrane-proximal region of the CD28 cytoplasmic domain. Thus, Nef probably induces CD28 endocytosis via the AP-2 pathway, and this involves a ternary complex containing Nef, AP-2 and CD28. The likely consequence of the concerted down-regulation of CD28, CD4 and/or CD3 by Nef is disruption of antigen-specific signaling machineries in infected T cells following a productive antigen recognition event.

Item Type: Paper
Uncontrolled Keywords: AP-2 clathrin adaptor CD28 lentivirus Nef T-cell activation IMMUNODEFICIENCY-VIRUS TYPE-1 T-CELL RECEPTOR CLATHRIN ADAPTER COMPLEXES HIV-1 NEF CD4 ENDOCYTOSIS DILEUCINE MOTIF BINDING SURFACE TRANSGENIC MICE I MOLECULES ZETA-CHAIN
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells

organism description > virus > lentivirus
CSHL Authors:
Communities: CSHL labs > Skowronski lab
Depositing User: Matt Covey
Date: April 2001
Date Deposited: 15 Jan 2014 21:53
Last Modified: 15 Jan 2014 21:53
PMCID: PMC145469
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29313

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