Distinct Functions of Tapasin Revealed by Polymorphism in MHC Class I Peptide Loading

Peh, Chen Au; Laham, Nihay; Burrows, Scott R.; Zhu, Yong; McCluskey, James

doi:10.4049/jimmunol.164.1.292

Cited by 51 publications

(60 citation statements)

References 43 publications

(50 reference statements)

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“…TAP interaction is mediated through the C terminus of tapasin (9) and has recently been shown to enhance peptide binding to the cytosolic aspect of TAP molecules (8). This implies that tapasin may enhance TAPmediated translocation of antigenic oligopeptides; however, bridging of class I molecules to the TAP does not necessarily lead to enhanced peptide loading (42,53). Therefore, it has been postulated that the class I-tapasin interaction is more critical for class I assembly than is the tapasin-mediated bridging to the TAP (9).…”

Section: Discussionmentioning

confidence: 99%

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Barnden

Purcell

Gorman³

et al. 2000

The Journal of Immunology

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The murine class I H-2Kb molecule achieves high level surface expression in tapasin-deficient 721.220 human cells. Compared with their behavior in wild-type cells, Kb molecules expressed on 721.220 cells are more receptive to exogenous peptide, undergo more rapid surface decay, and fail to form macromolecular peptide loading complexes. As a result, they are rapidly transported to the cell surface, reflecting a failure of endoplasmic reticulum retention mechanisms in the absence of loading complex formation. Despite the failure of Kb molecules to colocalize to the TAP and their rapid egress to the cell surface, Kb is still capable of presenting TAP-dependent peptides in the absence of tapasin. Furthermore, pool sequencing of peptides eluted from these molecules revealed strict conservation of their canonical H-2Kb-binding motif. There was a reduction in the total recovery of peptides associated with Kb molecules purified from the surface of tapasin-deficient cells. Comparison of the peptides bound to Kb in the presence and absence of tapasin revealed considerable overlap in peptide repertoire. These results indicate that in the absence of an interaction with tapasin, Kb molecules fail to assemble with calreticulin and TAP, yet they are still capable of acquiring a diverse array of peptides. However, a significant proportion of these peptides appear to be suboptimal, resulting in reduced cell surface stability of Kb complexes. Taken together, the findings indicate that tapasin plays an essential role in the formation of the class I loading complex, which retains class I heterodimers in the endoplasmic reticulum until optimal ligand selection is completed.

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Section: Discussionmentioning

confidence: 99%

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Barnden

Purcell

Gorman³

et al. 2000

The Journal of Immunology

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“…Much of the work examining tapasin function has understandably been performed using either tapasin-deficient cells (6,8,(40)(41)(42)(43)(44)(45) or mutant MHC class I molecules that no longer associate with tapasin (13,14,16,23,25). However, in tapasin-deficient cells, it is now apparent that TAPBPR is present and still capable of binding to MHC class I.…”

Section: Discussionmentioning

confidence: 99%

The Binding of TAPBPR and Tapasin to MHC Class I Is Mutually Exclusive

Hermann

Strittmatter

Deane

et al. 2013

The Journal of Immunology

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The loading of peptide antigens onto MHC class I molecules is a highly controlled process in which the MHC class I dedicated chaperone tapasin is a key player. We recently identified a tapasin related molecule, TAPBPR, as an additional component in the MHC class I antigen presentation pathway. Here we show that the amino acid residues important for tapasin to interact with MHC class I are highly conserved on TAPBPR. We identify specific residues in the N-terminal and C-terminal domains of TAPBPR involved in associating with MHC class I. Furthermore, we demonstrate that residues on MHC class I crucial for its association with tapasin, such as T134, are also essential for its interaction with TAPBPR. Taken together, the data indicate that TAPBPR and tapasin bind in a similar orientation to the same face of MHC class I. In the absence of tapasin, the association of MHC class I with TAPBPR is increased. However, in the absence of TAPBPR, the interaction between MHC class I and tapasin does not increase. In light of our findings, previous data determining the function of tapasin in the MHC class I antigen processing and presentation pathway must be re-evaluated.

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“…HLA class I alleles differ in their requirements for antigen processing components; for example, tumors frequently exhibit alterations in the levels of TAP1-2, LMP2, LMP7, or tapasin expression [22][23][24]. Some alleles, such as HLA-A2, maintain their expression despite low levels of TAP1-2 or tapasin [25,26], whereas others, such as HLA-B44, have strict requirements for certain antigen processing components [27][28][29]. These variations may explain the marked differences between HLA-A2 and HLA-B44 in the frequency of selective loss of expression in human tumors.…”

Section: Discussionmentioning

confidence: 99%

High frequency of HLA-B44 allelic losses in human solid tumors

et al. 2003

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Human leukocyte antigen (HLA) class I downregulation, a frequent phenomenon observed in a variety of human tumors, favors tumor immune escape from T-lymphocyte recognition. However, it is not known whether a particular HLA class I allele is lost more frequently than others. To address this question we analyzed HLA class I expression in tumor tissues derived from 300 patients diagnosed as having breast, colorectal, or laryngeal carcinomas. Cryostatic tumor sections and a broad panel of anti-HLA class I monoclonal antibodies were used. We found that the HLA-B44 allele was lost more frequently than other HLA class I alleles, and that the difference was not related with changes in HLA-B44 allele frequencies between patients and controls. In addition, we observed that 35% of the HLA-B44 negative tumors presented HLA haplotype loss associated with loss of heterozygosity. These tests were performed on DNA samples obtained from microdissected tumor tissues. The results seem to indicate that HLA class I allelic losses are not randomly distributed during tumor development but that some HLA class I alleles, and HLA-B44 in particular, are more frequently downregulated and may play an important role in immune escape mechanisms. Human Immunology 64, 941-950 (2003).

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Distinct Functions of Tapasin Revealed by Polymorphism in MHC Class I Peptide Loading

Cited by 51 publications

References 43 publications

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

The Binding of TAPBPR and Tapasin to MHC Class I Is Mutually Exclusive

High frequency of HLA-B44 allelic losses in human solid tumors

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