A Novel Trafficking Signal within the HLA-C Cytoplasmic Tail Allows Regulated Expression upon Differentiation of Macrophages

Schaefer, Malinda; Williams, Michael; Kulpa, Deanna A.; Blakely, Pennelope; Yaffee, Anna Q; Collins, Kathleen L.

doi:10.4049/jimmunol.180.12.7804

Cited by 49 publications

(54 citation statements)

References 42 publications

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“…These cells were stimulated with GM-CSF alone or GM-CSF, IL-4, and TNF-␣ to induce macrophage-or monocyte-derived dendritic cell phenotypes, respectively (76,94). We observed no significant effect of Nef on the surface expression of endogenous CD80 and CD86 in either cell type ( Fig.…”

Section: Resultsmentioning

confidence: 77%

HIV-1 Nef Disrupts Intracellular Trafficking of Major Histocompatibility Complex Class I, CD4, CD8, and CD28 by Distinct Pathways That Share Common Elements

Leonard

Filzen²,

Carter

et al. 2011

J Virol

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The Nef protein is an important HIV virulence factor that promotes the degradation of host proteins to augment virus production and facilitate immune evasion. The best-characterized targets of Nef are major histocompatibility complex class I (MHC-I) and CD4, but Nef also has been reported to target several other proteins, including CD8␤, CD28, CD80, CD86, and CD1d. To compare and contrast the effects of Nef on each protein, we constructed a panel of chimeric proteins in which the extracellular and transmembrane regions of the MHC-I allele HLA-A2 were fused to the cytoplasmic tails of CD4, CD28, CD8␤, CD80, CD86, and CD1d. We found that Nef coprecipitated with and disrupted the expression of molecules with cytoplasmic tails from MHC-I HLA-A2, CD4, CD8␤, and CD28, but Nef did not bind to or alter the expression of molecules with cytoplasmic tails from CD80, CD86, and CD1d. In addition, we used short interfering RNA (siRNA) knockdown and coprecipitation experiments to implicate AP-1 as a cellular cofactor for Nef in the downmodulation of both CD28 and CD8␤. The interaction with AP-1 required for CD28 and CD8␤ differed from the AP-1 interaction required for MHC-I downmodulation in that it was mediated through the dileucine motif within Nef (LL 164,165 AA) and did not require the tyrosine binding pocket of the AP-1 subunit. In addition, we demonstrate a requirement for ␤-COP as a cellular cofactor for Nef that was necessary for the degradation of targeted molecules HLA-A2, CD4, and CD8. These studies provide important new information on the similarities and differences with which Nef affects intracellular trafficking and help focus future research on the best potential pharmaceutical targets.

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Section: Resultsmentioning

confidence: 77%

HIV-1 Nef Disrupts Intracellular Trafficking of Major Histocompatibility Complex Class I, CD4, CD8, and CD28 by Distinct Pathways That Share Common Elements

Leonard

Filzen²,

Carter

et al. 2011

J Virol

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“…Increased cell surface expression of FHC is associated with the activation of lymphocytes (41)(42)(43)(44)(45)(46)(47) and potentially APCs (73). HLA-C is particularly prone to forming FHC due to its unusual stability in the absence of b 2 m (54,(74)(75)(76)(77), and this form of HLA-C is specifically upregulated during macrophage differentiation (78). Increased levels of FHC influence HLA class I clustering on activated T cells (44,79,80).…”

Section: Discussionmentioning

confidence: 99%

HLA Class I Allelic Sequence and Conformation Regulate Leukocyte Ig-Like Receptor Binding

Jones

Kosmoliaptsis

Apps

et al. 2011

The Journal of Immunology

110

143

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Leukocyte Ig-like receptors (LILRs) are a family of innate immune receptors predominantly expressed by myeloid cells that can alter the Ag presentation properties of macrophages and dendritic cells. Several LILRs bind HLA class I. Altered LILR recognition due to HLA allelic variation could be a contributing factor in disease. We comprehensively assessed LILR binding to >90 HLA class I alleles. The inhibitory receptors LILRB1 and LILRB2 varied in their level of binding to different HLA alleles, correlating in some cases with specific amino acid motifs. LILRB2 displayed the weakest binding to HLA-B*2705, an allele genetically associated with several autoimmune conditions and delayed progression of HIV infection. We also assessed the effect of HLA class I conformation on LILR binding. LILRB1 exclusively bound folded β2-microglobulin–associated class I, whereas LILRB2 bound both folded and free H chain forms. In contrast, the activating receptor LILRA1 and the soluble LILRA3 protein displayed a preference for binding to HLA-C free H chain. To our knowledge, this is the first study to identify the ligand of LILRA3. These findings support the hypothesis that LILR-mediated detection of unfolded versus folded MHC modulates immune responses during infection or inflammation.

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“…HLA-C molecules are expressed at a low level on the cell surface compared with HLA-A and -B (1)(2)(3)(4)(5), owing in part to the poor assembly of HLA-C heavy chains with β2 microglobulin (2,4) and the retention of HLA-C molecules in the endoplasmic reticulum, where they are partially degraded (3). An internalization and lysosomal targeting signal in the cytoplasmic tail of HLA-C further regulates its surface expression (6). Unlike HLA-A and -B, HLA-C surface expression is not down-regulated by Nef upon HIV infection (7).…”

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confidence: 99%

Genetic interplay betweenHLA-CandMIR148Ain HIV control and Crohn disease

Kulkarni

Ying

Ó'hUigín

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance In the human population different HLA-C allotypes are present that have different expression levels at the cell surface. Individuals with higher expressed HLA-C allotypes demonstrate better HIV control but increased risk of Crohn disease. A microRNA, miR-148a, regulates expression of some HLA-C allotypes. We report here that this microRNA also varies in expression level between people. MIR148A variation showed significant and opposing effects on HIV viral control vs. risk of Crohn disease, specifically in subjects with HLA-C alleles that are regulated by miR-148a. These results are independent of confounding effects by other HLA loci because only HLA-C is regulated by miR-148a. Our data represent an example of gene interactions that affect immune response and thereby the risk of human disease.

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A Novel Trafficking Signal within the HLA-C Cytoplasmic Tail Allows Regulated Expression upon Differentiation of Macrophages

Cited by 49 publications

References 42 publications

HIV-1 Nef Disrupts Intracellular Trafficking of Major Histocompatibility Complex Class I, CD4, CD8, and CD28 by Distinct Pathways That Share Common Elements

HIV-1 Nef Disrupts Intracellular Trafficking of Major Histocompatibility Complex Class I, CD4, CD8, and CD28 by Distinct Pathways That Share Common Elements

HLA Class I Allelic Sequence and Conformation Regulate Leukocyte Ig-Like Receptor Binding

Genetic interplay betweenHLA-CandMIR148Ain HIV control and Crohn disease

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