Major Histocompatibility Complex Class II-Peptide Complexes Internalize Using a Clathrin- and Dynamin-independent Endocytosis Pathway

Walseng, Even; Bakke, Oddmund; Roche, Paul A.

doi:10.1074/jbc.m801070200

Cited by 117 publications

(128 citation statements)

References 63 publications

(95 reference statements)

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“…These experimental problems were tackled in more recent experiments, from which we concluded that ubiquitination has little if any effect on the endocytosis rate of pMHCII (T ten Broeke, R Wubbolts, W Stoorvogel, et al, unpubl.). In contrast to MHCII -Ii complexes, pMHCII is endocytosed via clathrin-and dynamin-independent pathway(s), possibly involving SWAP-70-regulated RhoA/ RhoB (Ocana-Morgner et al 2009) or Arf6-and Rab35-dependent mechanism(s) (Walseng et al 2008). MHCII is found in detergent-resistant membrane domains (DRMs) (Anderson et al 2000;Karacsonyi et al 2004;Rodgers and Smith 2005), and endocytosis of MHCII was severely hampered after treatment of cells with Filipin, a cholesterol-sequestering agent (Knorr et al 2009).…”

Section: Trafficking Of Pmhciimentioning

confidence: 99%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

139

102

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For the initiation of adaptive immune responses, dendritic cells present antigenic peptides in association with major histocompatibility complex class II (MHCII) to naïve CD4 þ T lymphocytes. In this review, we discuss how antigen presentation is regulated through intracellular processing and trafficking of MHCII. Newly synthesized MHCII is chaperoned by the invariant chain to endosomes, where peptides from endocytosed pathogens can bind. In nonactivated dendritic cells, peptide-loaded MHCII is ubiquitinated and consequently sorted by the ESCRT machinery to intraluminal vesicles of multivesicular bodies, ultimately leading to lysosomal degradation. Ubiquitination of newly synthesized MHCII is blocked when dendritic cells are activated, now allowing its transfer to the cell surface. This mode of regulation for MHCII is a prime example of how molecular processing and sorting at multivesicular bodies can determine the expression of signaling receptors at the plasma membrane.

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Section: Trafficking Of Pmhciimentioning

confidence: 99%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

139

102

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“…(10,25,26). When clathrin-mediated endocytosis is inhibited by siRNAmediated knockdown of clathrin heavy-chain or AP-2 μ-chain, endocytosis of MHC-II-Ii complexes is prevented, and these complexes accumulate on the cell surface (10,25,26). By contrast, pMHC-II internalization is clathrin-independent and relatively slow, and involves passage of pMHC-II through Arf6 + Rab35 + endosomes (10).…”

Section: Mhc-ii Bound To II Endocytosis/sorting Mutants Is Effectivelymentioning

confidence: 99%

“…These results extend our analysis of MHC-II-Ii ubiquitination in cells expressing MHC-II and various forms of Ii and show that ubiquitination of MHC-II-Ii mutants by March-I results in rapid degradation of these complexes. (10,25,26). When clathrin-mediated endocytosis is inhibited by siRNAmediated knockdown of clathrin heavy-chain or AP-2 μ-chain, endocytosis of MHC-II-Ii complexes is prevented, and these complexes accumulate on the cell surface (10,25,26).…”

Section: Mhc-ii Bound To II Endocytosis/sorting Mutants Is Effectivelymentioning

confidence: 99%

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Internalizing MHC class II–peptide complexes are ubiquitinated in early endosomes and targeted for lysosomal degradation

Furuta

Walseng

Roche

2013

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

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As sentinels of the immune system, dendritic cells (DCs) continuously generate and turnover antigenic peptide-MHC class II complexes (pMHC-II). pMHC-II generation is a complex process that involves many well-characterized MHC-II biosynthetic intermediates; however, the mechanisms leading to MHC-II turnover/degradation are poorly understood. We now show that pMHC-II complexes undergoing clathrin-independent endocytosis from the DC surface are efficiently ubiquitinated by the E3 ubiquitin ligase March-I in early endosomes, whereas biosynthetically immature MHC-IIInvariant chain (Ii) complexes are not. The inability of MHC-II-Ii to serve as a March-I substrate is a consequence of Ii sorting motifs that divert the MHC-II-Ii complex away from March-I + early endosomes. When these sorting motifs are mutated, or when clathrin-mediated endocytosis is inhibited, MHC-II-Ii complexes internalize by using a clathrin-independent endocytosis pathway and are now ubiquitinated as efficiently as pMHC-II complexes. These data show that the selective ubiquitination of internalizing surface pMHC-II in March-I + early endosomes promotes degradation of "old" pMHC-II and spares forms of MHC-II that have not yet loaded antigenic peptides or have not yet reached the DC surface.D endritic cells (DCs) are professional antigen-presenting cells (APCs) that capture protein antigens by endocytosis and digest these internalized proteins into peptides in endo-/lysosomal compartments (1). These peptides are loaded onto MHC class II molecules (MHC-II) in antigen-processing compartments, and peptide-loaded MHC-II (pMHC-II) traffics to the DC plasma membrane. The interaction of specific pMHC-II on APCs with specific receptors on naïve CD4 T cells stimulates the activation and proliferation of CD4 T cells (1, 2). Each DC potentially expresses thousands of distinct pMHC-II complexes in which the MHC-II-bound peptides represent a sampling of the DC microenvironment.Resting (i.e., immature) DCs generate and express pMHC-II complexes on their surface, and, at steady state, the rates of MHC-II synthesis and degradation are equal. Stimulation of APCs, either by Toll-like receptor (TLR) ligands or by exposure to other "danger" signals, ultimately reduces the rate of MHC-II synthesis and prolongs MHC-II t 1/2 (3, 4), processes that allow the DC to preserve on their surface pMHC-II complexes generated at the time of DC activation. Given the importance of antigenic pMHC-II in the initiation of antigen-specific T cell responses, there is intense interest in elucidating the mechanisms regulating pMHC-II generation and turnover in professional APCs.Newly synthesized MHC-II αβ-dimers begin their transport to the plasma membrane by binding to a chaperone protein termed the invariant chain (Ii) in the ER (5). Most MHC-II-Ii complexes then leave the ER, traverse the Golgi apparatus, and are transported to cell surface. When they are at the cell surface, MHC-II-Ii complexes are rapidly internalized by clathrin-mediated endocytosis, pass through early endosomes, and a...

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“…We have readdressed the issue of DMmediated peptide exchange at the cell surface by using a dominant-negative form of dynamin (Dyn K44E). As opposed to DR, DM reaches the endosomes after its rapid clathrin-mediated internalization from the cell surface (20,21). Thus, transient expression of Dyn K44E causes the selective accumulation of DM at the plasma membrane (Fig.…”

Section: Dmy Increases Peptide Loadingmentioning

confidence: 99%

Forced Expression of HLA-DM at the Surface of Dendritic Cells Increases Loading of Synthetic Peptides on MHC Class II Molecules and Modulates T Cell Responses

Pezeshki

Côté

Azar

et al. 2011

The Journal of Immunology

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Adoptive transfer of autologous dendritic cells (DCs) loaded with tumor-associated CD4 and CD8 T cell epitopes represents a promising avenue for the immunotherapy of cancer. In an effort to increase the loading of therapeutic synthetic peptides on MHC II molecules, we used a mutant of HLA-DM (DMY) devoid of its lysosomal sorting motif and that accumulates at the cell surface. Transfection of DMY into HLA-DR+ cells resulted in increased loading of the exogenously supplied HA307–318 peptide, as well as increased stimulation of HA-specific T cells. Also, on transduction in mouse and human DCs, DMY increased loading of HEL48–61 and of the tumor Ag-derived gp100174–190 peptides, respectively. Interestingly, expression of DMY at the surface of APCs favored Th1 differentiation over Th2. Finally, we found that DMY− and DMY+ mouse APCs differentially stimulated T cell hybridomas sensitive to the fine conformation of peptide–MHC II complexes. Taken together, our results suggest that the overexpression of HLA-DMY at the plasma membrane of DCs may improve quantitatively, but also qualitatively, the presentation of CD4 T cell epitopes in cellular vaccine therapies for cancer.

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Major Histocompatibility Complex Class II-Peptide Complexes Internalize Using a Clathrin- and Dynamin-independent Endocytosis Pathway

Cited by 117 publications

References 63 publications

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Internalizing MHC class II–peptide complexes are ubiquitinated in early endosomes and targeted for lysosomal degradation

Forced Expression of HLA-DM at the Surface of Dendritic Cells Increases Loading of Synthetic Peptides on MHC Class II Molecules and Modulates T Cell Responses

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