Interaction of MHC class II molecules with the invariant chain: role of the invariant chain (81–90) region

Stumptner, Pamela; Benaroch, Philippe

doi:10.1038/sj.emboj.7590555

Cited by 54 publications

(36 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Peptide mapping studies and nuclear magnetic resonance methods demonstrate that the class II binding segment of Ii chain encompasses residues 72-110 (62,63), but the peptide groove accommodates only the core CLIP sequence comprised of residues 91-99 (64). Considerable data suggest that adjacent regions of the Ii chain modulate class II associations (65,66). The segment N-terminal to Met 91 appears to bind an effector site outside the groove and may act allosterically to enhance peptide exchange and CLIP release (48).…”

Section: Discussionmentioning

confidence: 99%

DM Loss in k Haplotype Mice Reveals Isotype-Specific Chaperone Requirements

Koonce

Wutz

Robertson

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

DM actions as a class II chaperone promote capture of diverse peptides inside the endocytic compartment(s). DM mutant cells studied to date express class II bound by class II-associated invariant chain-derived peptide (CLIP), a short proteolytic fragment of the invariant chain, and exhibit defective peptide-loading abilities. To evaluate DM functional contributions in k haplotype mice, we engineered a novel mutation at the DMa locus via embryonic stem cell technology. The present experiments demonstrate short-lived Ak/CLIP complexes, decreased Ak surface expression, and enhanced Ak peptide binding activities. Thus, we conclude that DM loss in k haplotype mice creates a substantial pool of empty or loosely occupied Ak conformers. On the other hand, the mutation hardly affects Ek activities. The appearance of mature compact Ek dimers, near normal surface expression, and efficient Ag presentation capabilities strengthen the evidence for isotype-specific DM requirements. In contrast to DM mutants described previously, partial occupancy by wild-type ligands is sufficient to eliminate antiself reactivity. Mass spectrometry profiles reveal Ak/CLIP and a heterogeneous collection of relatively short peptides bound to Ek molecules. These experiments demonstrate that DM has distinct roles depending on its specific class II partners.

show abstract

Section: Discussionmentioning

confidence: 99%

DM Loss in k Haplotype Mice Reveals Isotype-Specific Chaperone Requirements

Koonce

Wutz

Robertson

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…During their assembly in the endoplasmic reticulum (ER), class-II ␣␤ dimers associate with preformed trimers of the invariant chain (Ii) to form nonameric (␣␤Ii) 3 oligomers (Marks et al, 1990;Roche et al, 1991;Lamb and Cresswell, 1992). Ii folds in part through the peptide-binding groove and promotes the folding of class-II molecules by preventing aggregation and premature binding of endogenously synthesized peptides (Roche and Cresswell, 1990;Romagnoli and Germain, 1994;Stumptner and Benaroch, 1997;Busch et al, 1996;Anderson and Miller, 1992;Hitzel and Koch, 1996). Targeting of the complex to the endocytic pathway is mediated by two leucine-based motifs in the cytoplasmic tail of Ii (Pieters et al, 1993;Odorizzi et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

A three-amino-acid-long HLA-DRβ cytoplasmic tail is sufficient to overcome ER retention of invariant-chain p35

Khalil

Brunet

Thibodeau

2005

Journal of Cell Science

View full text Add to dashboard Cite

the Iip35 RXR motif. Moreover, replacement of residues F231 and R232 with alanines created a cytoplasmic tail (Tyr-Ala-Ala) that allowed ER egress. Given the limited length of this tail, steric hindrance would only be possible if the Ii ER retention motif was close to the membrane in the first place. However, this is not likely because an Ii molecule with an internal cytoplasmic deletion bringing the RXR motif closer to the membrane is not retained in the ER, even in the absence of class-II molecules. These results suggest that MHC-class-II molecules overcome ER retention and prevent COPI binding to the Iip35 RXR motif through a mechanism distinct from steric hindrance by its ␤ ␤ chain.

show abstract

“…Following their synthesis, the ␣ and ␤ subunits of the class II molecule associate in the endoplasmic reticulum (ER) together with the invariant chain (Ii) (2). The latter folds in part through the groove of the class II molecule, stabilizing the ␣␤ heterodimer and preventing the undesirable binding of ER polypeptides (3)(4)(5)(6). Studies using mice with inactivated Ii genes suggested that Ii is necessary for efficient exit of newly synthesized class II molecules from the ER (7,8).…”

mentioning

confidence: 99%

Functional Characterization of a Lysosomal Sorting Motif in the Cytoplasmic Tail of HLA-DOβ

Brunet¹,

Samaan²,

Deshaies³

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

HLA-DO is an intracellular non-classical class II major histocompatibility complex molecule expressed in the endocytic pathway of B lymphocytes, which regulates the loading of antigenic peptides onto classical class II molecules such as HLA-DR. The activity of HLA-DO is mediated through its interaction with the peptide editor HLA-DM. Here, our results demonstrate that although HLA-DO is absolutely dependent on its association with DM to egress the endoplasmic reticulum, the cytoplasmic portion of its ␤ chain encodes a functional lysosomal sorting signal. By confocal microscopy and flow cytometry analysis, we show that reporter transmembrane molecules fused to the cytoplasmic tail of HLA-DO␤ accumulated in Lamp-1 ؉ vesicles of transfected HeLa cells. Mutagenesis of a leucine-leucine motif abrogated lysosomal accumulation and resulted in cell surface redistribution of reporter molecules. Finally, we show that mutation of the di-leucine sequence in DO␤ did not alter its lysosomal sorting when associated with DM molecules. Taken together, these results demonstrate that lysosomal expression of the DO-DM complex is mediated primarily by the tyrosine-based motif of HLA-DM and suggest that the DO␤-encoded motif is involved in the fine-tuning of the intracellular sorting. Major histocompatibility complex (MHC)1 class II molecules are heterodimeric cell surface glycoproteins that present antigens to CD4 ϩ T cells (1). The antigenic peptide-class II complexes are expressed on specialized antigen-presenting cells such as macrophages and B lymphocytes. Following their synthesis, the ␣ and ␤ subunits of the class II molecule associate in the endoplasmic reticulum (ER) together with the invariant chain (Ii) (2). The latter folds in part through the groove of the class II molecule, stabilizing the ␣␤ heterodimer and preventing the undesirable binding of ER polypeptides (3-6). Studies using mice with inactivated Ii genes suggested that Ii is necessary for efficient exit of newly synthesized class II molecules from the ER (7, 8). However, it was later demonstrated that high levels of class II molecules reach the surface of Ii Ϫ dendritic cells (9). Moreover, transfected cells express a substantial amount of class II molecules at their plasma membrane even in the absence of Ii (10). Such a phenotype probably results from the binding of endogenous peptides or polypeptides present in the ER (6, 11) and supports the notion that occupancy of the peptide-binding groove is sufficient to allow ER egress (12).Another function of Ii is to direct efficiently MHC class II molecules to the endocytic antigen-loading compartments (13-15). Two short leucine-based sequences located in the cytoplasmic tail of Ii are responsible for trafficking through the endocytic pathway (16,17). Similar motifs in many proteins are specifically recognized at the cell surface and trans-Golgi by elements of the sorting machinery (reviewed in Ref. 18).Once the class II-Ii complex reaches the endosomal compartments, the invariant chain is progressively degraded by v...

show abstract

Interaction of MHC class II molecules with the invariant chain: role of the invariant chain (81–90) region

Cited by 54 publications

References 59 publications

DM Loss in k Haplotype Mice Reveals Isotype-Specific Chaperone Requirements

DM Loss in k Haplotype Mice Reveals Isotype-Specific Chaperone Requirements

A three-amino-acid-long HLA-DRβ cytoplasmic tail is sufficient to overcome ER retention of invariant-chain p35

Functional Characterization of a Lysosomal Sorting Motif in the Cytoplasmic Tail of HLA-DOβ

Contact Info

Product

Resources

About