Invariant chain protects class II histocompatibility antigens from binding intact polypeptides in the endoplasmic reticulum.

Busch, Robert; Cloutier, Isabelle; Sékaly, Rafick Pierre; Hämmerling, Günter J.

doi:10.1002/j.1460-2075.1996.tb00372.x

Cited by 138 publications

(92 citation statements)

References 63 publications

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“…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).…”

mentioning

confidence: 72%

“…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).…”

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confidence: 99%

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

Brunet¹,

Samaan²,

Deshaies³

et al. 2000

Journal of Biological Chemistry

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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...

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confidence: 72%

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

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“…In the absence of Ii, DR molecules may route to the endosomes via the cell surface or directly from the ER by using the DR␤ chain dileucine endosomal targeting motif (38). The ability to enter the endosomal pathway in the absence of Ii appears to be cell type specific (37,39). Two very recent in vivo studies in mice have supported the concept that altered routing of class II (38) or the absence of Ii (40) generates cell surface class II-peptide complexes that differ from those on conventional APC and alter T cell antigen-and allo-reactivity.…”

Section: Discussionmentioning

confidence: 99%

In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM

Lightstone¹,

Hargreaves²,

Bobek³

et al. 1997

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

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The independent inf luences of invariant chain (Ii) and HLA-DM molecules on the array of naturally processed peptides displayed by HLA-DR molecules were studied using transfected cell lines. Major histocompatibility complex (MHC) class II molecules present peptide antigens to MHC class II-restricted CD4 ϩ T cells. The peptides presented are usually derived from internalized exogenous or membrane-bound proteins (1) which are unfolded, denatured, and degraded within the progressively acidic endosomal pathway. Class II molecules are assembled in the endoplasmic reticulum (ER), where they associate noncovalently with the invariant chain (Ii), a type 2 transmembrane protein (reviewed in ref.2). The CLIP region of Ii (amino acids 81-104) binds in the groove of nascent MHC class II molecules, thereby inhibiting the binding of peptides in the ER (3-5). An endosomal targeting motif within the amino terminus of the p33 form of Ii directs the Ii-class II complexes to specialized endosomal compartments, MIIC (6, 7). Here, Ii is sequentially degraded by proteases, and the catalytic activity of HLA-DM promotes exchange of CLIP for peptides derived from endocytosed proteins (8-11).In the absence of Ii, as shown in Ii knockout mice (Ii 0/0 ), few class II molecules reach the cell surface, as most are retained in the ER and degraded (12, 13). The studies of antigen presentation by Ii-negative (Ii Ϫ ) cells reported to date have largely used T cell clones or hybridomas raised against conventional antigen-presenting cells (APC) as responders. The results of such studies have shown that a degree of overlap exists between the peptides displayed by MHC class II molecules expressed in the presence and the absence of Ii (for example, see ref. 14). However, this approach does not inform whether the complete or relative absence of Ii leads to the display of novel peptide epitopes by MHC class II molecules, an important issue if circumstances can arise in vivo in which Ii is limiting in MHC class II ϩ cells.In this study we used alloreactive T cell clones as probes of peptide occupancy of class II molecules expressed in the presence or absence of Ii and HLA-DM on the basis that anti-MHC allorecognition generally involves the corecognition of the allogeneic MHC molecule and bound peptide (for review see ref. 15). The results suggest that in the absence of Ii, MHC class II molecules display a distinct array of peptides. Furthermore, HLA-DM influenced allorecognition of DR molecules in the absence of Ii, suggesting that HLA-DM can influence MHC class II peptide occupancy independently of Ii. Taken together, these findings support the prediction that discordant regulation of MHC class II, Ii, and HLA-DM molecules in vivo, as has been observed in bone marrow macrophages (16) and in gut epithelial cells (17) for MHC and Ii, could lead to the display of self-peptides to which the T cell repertoire is not tolerant.

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“…Although MHCII a chains and b chains already assemble and form peptide-binding sites in the ER, they capture peptides only after arriving at the endocytic pathway. Premature peptide loading is prevented by the invariant chain (Ii, also called CD74) (Teyton et al 1990;Busch et al 1996). Ii binds the MHCII peptide-binding groove with a region in its luminal domain that is called CLIP (for class-II-associated invariant chain peptide) (Rudensky et al 1991;Chicz et al 1992;Riberdy et al 1992;Sette et al 1992;Freisewinkel et al 1993).…”

Section: Biosynthesis Of Mhciimentioning

confidence: 99%

“…Normally, Ii is synthesized in excess over MHCII, ensuring Ii rather than peptide binding to MHCII (Kvist et al 1982;Sekaly et al 1986;Marks et al 1990;Pieters et al 1991). Peptides that are transferred into the ER by TAP, for potential binding to MHCI, indeed have poor potential to bind MHCII (Bikoff et al 1993;Viville et al 1993;Elliott et al 1994;Romagnoli and Germain 1994;Busch et al 1996). Ii is encoded outside the MHC gene region, but its expression, like MHCII, is under the control of CIITA (Reith et al 2005).…”

Section: Biosynthesis Of Mhciimentioning

confidence: 99%

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

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

143

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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Invariant chain protects class II histocompatibility antigens from binding intact polypeptides in the endoplasmic reticulum.

Cited by 138 publications

References 63 publications

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

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

In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM

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

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