How MHC Class II Molecules Acquire Peptide Cargo: Biosynthesis and Trafficking through the Endocytic Pathway

Wolf, Paula; Ploegh, Hidde L.

doi:10.1146/annurev.cb.11.110195.001411

Cited by 249 publications

(122 citation statements)

References 75 publications

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“…In addition, IiP25 includes the CLIP region that is responsible for binding to MHC class II molecules (26). One important function of Ii is to target the MHC class II complex to endocytic organelles (1,3). The targeting sequences responsible for endosomal location reside in the N-terminal cytoplasmic tail (9,11,12).…”

Section: Resultsmentioning

confidence: 99%

“…Aliquots of 100 ml were incubated for 1 h at 4°C with the bifunctional chemical cross-linker BS 3 (Pierce) at the concentrations indicated. Excess cross-linker was quenched with 100 mM glycine, pH 8.5, for 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…MHC class II molecules present antigenic peptides to CD4-positive T cells, and these peptides are usually derived from antigens that are internalized and processed in the endosomal/lysosomal pathway (2,3). Directly after translation and insertion into the endoplasmic reticulum membrane, the ␣␤ molecules associate with a third molecule, the invariant chain (Ii).…”

mentioning

confidence: 99%

See 2 more Smart Citations

A Secreted Form of the Major Histocompatibility Complex Class II-associated Invariant Chain Inhibiting T Cell Activation

Eynon¹,

Schlax²,

Pieters³

1999

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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A Secreted Form of the Major Histocompatibility Complex Class II-associated Invariant Chain Inhibiting T Cell Activation

Eynon¹,

Schlax²,

Pieters³

1999

Journal of Biological Chemistry

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“…BCR-Ag complexes first enter early endosomes and are targeted to late endocytic compartments where they are degraded in peptides (3,4). These peptides are then loaded onto MHC class II and the complexes are displayed at the surface of Ag presenting cells (2,5,6). Peptide loading occurs mostly in late endocytic compartments, called the MHC class II-enriched compartment, an endocytic multivesicular and/or multilaminar structure, which bears markers of late endosome (7)(8)(9).…”

Section: Binding Of Antigens (Ag)mentioning

confidence: 99%

Phosphoinositide 3-Kinase Activation by Igβ Controls de Novo Formation of an Antigen-processing Compartment

Granboulan¹,

Lankar²,

Raposo³

et al. 2003

Journal of Biological Chemistry

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Antigens that bind B cell antigen receptor (BCR) are preferentially and rapidly processed for antigen presentation. The BCR is a multimeric complex containing a signaling module composed of Ig␣ and Ig␤. Signaling pathways implicated in antigen presentation through the BCR are ill defined. Here we demonstrate that phosphoinositide 3-kinase (PI3K) inhibitors preclude antigen presentation induced by BCR or Ig␤ but not Ig␣. Unraveling the mechanisms responsible for this inhibition, we show that PI3K inhibitors block neither antigen internalization nor degradation. Rather PI3K inhibitors block de novo formation of a multivesicular antigen processing compartment, which is induced by triggering of the BCR or Ig␤. Strikingly, we found using fluorescent probes binding specifically to PI3K products that BCR and Ig␤ but not Ig␣ induce PI3K activation in endocytic compartments wherein antigen is transported. Altogether, these results strongly suggest that Ig␤ couples the BCR to PI3K activation that is instrumental for de novo formation of the antigen processing compartment and efficient antigen presentation.

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“…Newly synthesized MHC-IIs associated with the invariant chains (Iis) are transported to a late endocytic compartment where the Ii is removed by proteolytic cleavage, leaving the class II Ii-derived peptide (CLIP) bound to the peptide-binding groove (1,2). This is followed by peptide editing, which is catalyzed by the MHC-encoded DM molecule (3)(4)(5)(6). The initial forms of antigen that bind to MHC-IIs may be short peptides, 12-26 aa in length, generated by lysosomal proteases (7,8).…”

mentioning

confidence: 99%

Folding of an MHC class II-restricted tumor antigen controls its antigenicity via MHC-guided processing

Mimura

Mimura‐Kimura

Doores

et al. 2007

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

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antigen presentation ͉ immunodominance ͉ protein folding T wo antigen-processing pathways have been described for the loading of MHC class II molecules (MHC-IIs) with peptides for presentation to CD4 ϩ T cells. In the classical pathway, exogenous antigens taken up by antigen-presenting cells (APCs) are unfolded and cleaved into fragments during transport through the increasingly acidic endosomal network, from early endosomes to lysosomes. Newly synthesized MHC-IIs associated with the invariant chains (Iis) are transported to a late endocytic compartment where the Ii is removed by proteolytic cleavage, leaving the class II Ii-derived peptide (CLIP) bound to the peptide-binding groove (1, 2). This is followed by peptide editing, which is catalyzed by the MHC-encoded DM molecule (3-6). The initial forms of antigen that bind to MHC-IIs may be short peptides, 12-26 aa in length, generated by lysosomal proteases (7,8). A second pathway has been described in which mature MHC-IIs recycle from the cell surface to early endosomes and load antigenic peptides that are made available in less acidic and less aggressively proteolytic environments, independently of newly synthesized MHC-IIs, Iis, and DM molecules (9-12).A long-standing question concerning antigen processing in the MHC class II pathway is whether peptides are always generated first and then loaded (trim/bind model) or whether epitopes can be generated after the binding of intact antigen to MHC-IIs (bind/trim model) (13-16). The former model has been presumed to prevail, but Sercarz et al. (13,14) have suggested that immunodominant epitopes within an intact, partially unfolding antigen might first bind to MHC-IIs and subsequently be trimmed to short peptide epitopes that roughly corresponded to the ''footprint'' of the MHC binding site. This latter model, or MHC-guided processing, has its roots in reports of MHC-IIs binding to long polypeptides (17-19). It remains unclear, however, whether these large polypeptides were the precursors of immunogenic peptides or whether they were presented as large polypeptides. The structure of several MHC-II/peptide complexes has now been solved, and it seems likely that peptides preferentially interact with the peptide-binding groove in an extended conformation, although some ''bulging'' is permitted for certain MHC-II/peptide combinations (20, 21). These data preclude the binding of MHC-IIs to elements of a protein antigen containing significant secondary structure. One mechanism by which large proteins or polypeptides bind to MHC-IIs might therefore be solvent-exposed regions of eight or more amino acids that adopt an extended or random conformation. Several proteins are known to display a more ''relaxed'' conformation during either thermal or chemical denaturation or during biogenesis. The latter may therefore give rise to a pool of substrates capable of binding to MHC-IIs and engaging in MHC-guided processing.Here we describe how the notion of MHC-guided processing is related to the immunodominance of a recently identified M...

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How MHC Class II Molecules Acquire Peptide Cargo: Biosynthesis and Trafficking through the Endocytic Pathway

Cited by 249 publications

References 75 publications

A Secreted Form of the Major Histocompatibility Complex Class II-associated Invariant Chain Inhibiting T Cell Activation

A Secreted Form of the Major Histocompatibility Complex Class II-associated Invariant Chain Inhibiting T Cell Activation

Phosphoinositide 3-Kinase Activation by Igβ Controls de Novo Formation of an Antigen-processing Compartment

Folding of an MHC class II-restricted tumor antigen controls its antigenicity via MHC-guided processing

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