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HIV-1 Nef disrupts MHC-I trafficking by recruiting AP-1 to the MHC-I cytoplasmic tail.

Roeth JF, Williams M, Kasper MR, Filzen TM, Collins KL - J. Cell Biol. (2004)

Bottom Line: We demonstrate that in HIV-infected primary T cells, Nef promotes a physical interaction between endogenous AP-1 and MHC-I.Moreover, we present data that this interaction uses a novel AP-1 binding site that requires amino acids in the MHC-I cytoplasmic tail.In sum, our evidence suggests that binding of AP-1 to the Nef-MHC-I complex is an important step required for inhibition of antigen presentation by HIV.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA.

ABSTRACT
To avoid immune recognition by cytotoxic T lymphocytes (CTLs), human immunodeficiency virus (HIV)-1 Nef disrupts the transport of major histocompatibility complex class I molecules (MHC-I) to the cell surface in HIV-infected T cells. However, the mechanism by which Nef does this is unknown. We report that Nef disrupts MHC-I trafficking by rerouting newly synthesized MHC-I from the trans-Golgi network (TGN) to lysosomal compartments for degradation. The ability of Nef to target MHC-I from the TGN to lysosomes is dependent on expression of the mu1 subunit of adaptor protein (AP) AP-1A, a cellular protein complex implicated in TGN to endolysosomal pathways. We demonstrate that in HIV-infected primary T cells, Nef promotes a physical interaction between endogenous AP-1 and MHC-I. Moreover, we present data that this interaction uses a novel AP-1 binding site that requires amino acids in the MHC-I cytoplasmic tail. In sum, our evidence suggests that binding of AP-1 to the Nef-MHC-I complex is an important step required for inhibition of antigen presentation by HIV.

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Model for MHC-I trafficking in Nef-expressing T cells. To disrupt MHC-I trafficking, Nef first binds to the MHC-I cytoplasmic tail in the secretory pathway. The formation of the Nef–MHC-I complex creates a binding site for AP-1 that is independent of the Nef dileucine motif. This tertiary complex leads to the recruitment of MHC-I into AP-1–positive clathrin-coated vesicles destined for degradation in the lysosomes.
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fig7: Model for MHC-I trafficking in Nef-expressing T cells. To disrupt MHC-I trafficking, Nef first binds to the MHC-I cytoplasmic tail in the secretory pathway. The formation of the Nef–MHC-I complex creates a binding site for AP-1 that is independent of the Nef dileucine motif. This tertiary complex leads to the recruitment of MHC-I into AP-1–positive clathrin-coated vesicles destined for degradation in the lysosomes.

Mentions: The normal function of AP-1 is to sort proteins, such as lysosomal enzyme receptors at the TGN by linking clathrin to the cytoplasmic tails of cargo (for review see Dell'Angelica and Payne, 2001; Robinson and Bonifacino, 2001; Traub, 2003; Robinson, 2004). For example, the mannose 6-phosphate receptor (MPR), which binds soluble lysosomal enzymes, is sorted at the TGN by AP-1. It is then transported in vesicles to endosomes where the enzymes dissociate and are carried to the lysosomes. The MPRs are then recycled back to the TGN to transport more cargo. Thus, Nef-induced AP-1 binding of MHC-I would be expected to promote TGN accumulation and/or targeting of MHC-I into the endolysosomal pathway (Fig. 7).


HIV-1 Nef disrupts MHC-I trafficking by recruiting AP-1 to the MHC-I cytoplasmic tail.

Roeth JF, Williams M, Kasper MR, Filzen TM, Collins KL - J. Cell Biol. (2004)

Model for MHC-I trafficking in Nef-expressing T cells. To disrupt MHC-I trafficking, Nef first binds to the MHC-I cytoplasmic tail in the secretory pathway. The formation of the Nef–MHC-I complex creates a binding site for AP-1 that is independent of the Nef dileucine motif. This tertiary complex leads to the recruitment of MHC-I into AP-1–positive clathrin-coated vesicles destined for degradation in the lysosomes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172469&req=5

fig7: Model for MHC-I trafficking in Nef-expressing T cells. To disrupt MHC-I trafficking, Nef first binds to the MHC-I cytoplasmic tail in the secretory pathway. The formation of the Nef–MHC-I complex creates a binding site for AP-1 that is independent of the Nef dileucine motif. This tertiary complex leads to the recruitment of MHC-I into AP-1–positive clathrin-coated vesicles destined for degradation in the lysosomes.
Mentions: The normal function of AP-1 is to sort proteins, such as lysosomal enzyme receptors at the TGN by linking clathrin to the cytoplasmic tails of cargo (for review see Dell'Angelica and Payne, 2001; Robinson and Bonifacino, 2001; Traub, 2003; Robinson, 2004). For example, the mannose 6-phosphate receptor (MPR), which binds soluble lysosomal enzymes, is sorted at the TGN by AP-1. It is then transported in vesicles to endosomes where the enzymes dissociate and are carried to the lysosomes. The MPRs are then recycled back to the TGN to transport more cargo. Thus, Nef-induced AP-1 binding of MHC-I would be expected to promote TGN accumulation and/or targeting of MHC-I into the endolysosomal pathway (Fig. 7).

Bottom Line: We demonstrate that in HIV-infected primary T cells, Nef promotes a physical interaction between endogenous AP-1 and MHC-I.Moreover, we present data that this interaction uses a novel AP-1 binding site that requires amino acids in the MHC-I cytoplasmic tail.In sum, our evidence suggests that binding of AP-1 to the Nef-MHC-I complex is an important step required for inhibition of antigen presentation by HIV.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA.

ABSTRACT
To avoid immune recognition by cytotoxic T lymphocytes (CTLs), human immunodeficiency virus (HIV)-1 Nef disrupts the transport of major histocompatibility complex class I molecules (MHC-I) to the cell surface in HIV-infected T cells. However, the mechanism by which Nef does this is unknown. We report that Nef disrupts MHC-I trafficking by rerouting newly synthesized MHC-I from the trans-Golgi network (TGN) to lysosomal compartments for degradation. The ability of Nef to target MHC-I from the TGN to lysosomes is dependent on expression of the mu1 subunit of adaptor protein (AP) AP-1A, a cellular protein complex implicated in TGN to endolysosomal pathways. We demonstrate that in HIV-infected primary T cells, Nef promotes a physical interaction between endogenous AP-1 and MHC-I. Moreover, we present data that this interaction uses a novel AP-1 binding site that requires amino acids in the MHC-I cytoplasmic tail. In sum, our evidence suggests that binding of AP-1 to the Nef-MHC-I complex is an important step required for inhibition of antigen presentation by HIV.

Show MeSH
Related in: MedlinePlus