The SH3 domain-binding surface and an acidic motif in HIV-1 Nef regulate trafficking of class I MHC complexes

Greenberg, Michael E.; Iafrate, A. John; Skowroński, Jacek

doi:10.1093/emboj/17.10.2777

Cited by 280 publications

(363 citation statements)

References 82 publications

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“…For example, HIV-1 can increase cellular endocytosis of HLA molecules via nef 45,46 , limit HLA transcription and peptide processing via tat 47,48 and suppress TAP-mediated peptide transport into the endoplasmic reticulum 49 . Under selection pressure from the immune system, HIV-1 also mutates rapidly to evade cytotoxic T lymphocyte responses.…”

Section: Discussionmentioning

confidence: 99%

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Pymm

Illing

Ramarathinam

et al. 2017

Nat Struct Mol Biol

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Section: Discussionmentioning

confidence: 99%

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Pymm

Illing

Ramarathinam

et al. 2017

Nat Struct Mol Biol

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“…In the case of HIV-1, the Nef protein down-regulates cell surface MHC class I by accelerating the endocytosis of class I complexes (51)(52)(53)(54). The specific targeting of HLA-A and -B locus products, but not HLA-C or -E locus products, may be relevant for NK cell evasion (55). We proposed here that inhibition of MHC class I Ag presentation without significant reduction of cell surface class I levels, as observed here, could be another important mechanism.…”

Section: Discussionmentioning

confidence: 99%

Direct Priming and Cross-Priming Contribute Differentially to the Induction of CD8+ CTL Following Exposure to Vaccinia Virus Via Different Routes

Shen¹,

Wong

Buck

et al. 2002

The Journal of Immunology

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To explore the relative importance of direct presentation vs cross-priming in the induction of CTL responses to viruses and viral vectors, we generated a recombinant vaccinia vector, vUS11, expressing the human CMV (HCMV) protein US11. US11 dislocates most allelic forms of human and murine MHC class I heavy chains from the lumen of the endoplasmic reticulum into the cytosol, where they are degraded by proteasomes. Expression of US11 dramatically decreased the presentation of viral Ag and CTL recognition of infected cells in vitro without significantly reducing total cell surface MHC class I levels. However, because US11 is an endoplasmic reticulum resident membrane protein, it cannot block presentation by non-infected cells that take up Ag through the cross-priming pathway. We show that the expression of US11 strongly inhibits the induction of primary CD8+ CTLs when the infection occurs via the i.p. or i.v. route, demonstrating that direct priming is critical for the induction of CTL responses to viral infections introduced via these routes. This effect is less dramatic following i.m. infection and is minimal after s.c. or intradermal infection. Thus, classic MHC class I Ag presentation and cross-priming contribute differentially to the induction of CD8+ CTLs following exposure to vaccinia virus via different routes.

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“…Indeed, Nef down-regulates cell-surface receptors [31][32][33], interferes with signal transduction pathways [19,[26][27][28] and enhances virion infectivity and viral production [17]. Here, we present evidence for a novel function of Nef, the down-regulation of GM1 at the plasma membrane.…”

Section: Discussionmentioning

confidence: 81%

“…More recently, the subunit H of the V-ATPase has been described to bind to the medium chain of AP-2 and to connect Nef to the endocytic machinery [45]. Finally; residues of the N-terminal region favor the association of Nef with proteins important for MHC I down-regulation [31,33]. Therefore, although the exocytic and endocytic pathways regulating GM1 content at cell surface are not known, we can conjecture that the GM1 decrease at the plasma membrane of Nef expressing cells could result from an increased rate of endocytosis.…”

Section: Discussionmentioning

confidence: 99%

“…In T cells, GM1 is localized in intracellular compartments and is released to the plasma membrane following TCR and CD28 engagement [8]. Therefore, it is conceivable that Nef, which has been described to interact with many components of the cytoskeletal machinery by regulating the constitutive endocytosis of CD4 and MHC class I molecules [31][32][33], may interfere with the exocytic/endocytic trafficking of GM1. To test this hypothesis, Jurkat T cells were either infected with the VSV-G pseudotyped HIV-1 NL4-3 ( Fig.…”

Section: Hiv-1 Nef Down-regulates Membrane Gm1 Inmentioning

confidence: 99%

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Vav exchange factor counteracts the HIV‐1 Nef‐mediated decrease of plasma membrane GM1 and NF‐AT activity in T cells

et al. 2003

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Several findings support the importance of GM1-enriched lipid microdomains of plasma membrane and of Vav, an essential regulator of actin cytoskeletal rearrangement, in the regulation of T cell activation. Moreover, a functional link among lipid microdomains, Vav and the HIV product Nef has been described. These observations suggest that Nef can modify plasma membrane GM1, affecting the behavior of HIV-infected cells towards antigen recognition and Vav towards counteracting such an effect. We observed that Nef expression, either following viral infection or ectopic expression, significantly decreased the level of plasma membrane GM1 in unstimulated T cells. This down-regulation was associated with the inhibition of NF-AT activation, but not with NF-‹ B activation induced by TCR engagement. Dissecting the signaling pathway that regulates NF-AT activation, we found that Nef inhibited exclusively the Ca 2+ /calcineurin cascade, whereas the JNK cascade and AP-1 transcriptional activity were not affected. Our evidence that Vav overexpression counteracted both the Nef-induced decrease of GM1 expression and the inhibition of NF-AT activity, suggests a novel mechanism by which Nef may interfere with TCR-mediated activation through the modulation of intracellular trafficking and clustering of GM1-enriched microdomains at the cell surface.

show abstract

The SH3 domain-binding surface and an acidic motif in HIV-1 Nef regulate trafficking of class I MHC complexes

Cited by 280 publications

References 82 publications

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Direct Priming and Cross-Priming Contribute Differentially to the Induction of CD8+ CTL Following Exposure to Vaccinia Virus Via Different Routes

Vav exchange factor counteracts the HIV‐1 Nef‐mediated decrease of plasma membrane GM1 and NF‐AT activity in T cells

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