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

Barnden, Megan; Purcell, Anthony W.; Gorman, Jeffrey J.; McCluskey, James

doi:10.4049/jimmunol.165.1.322

Cited by 92 publications

(94 citation statements)

References 53 publications

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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%

“…Tapasin simultaneously binds to peptide-receptive MHC class I heterodimers and to TAP, localizing MHC class I to a concentrated source of newly degraded antigenic peptides (1)(2)(3)(4)(5). There is also evidence that tapasin optimizes or edits the peptides presented on MHC class I by facilitating exchange of suboptimal peptides for higher-affinity cargo (6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…3A). Various groups have suggested that tapasin retains empty or poorly loaded (and therefore unstable) MHC-I molecules in the ER until proper peptide loading is accomplished (29,33). In the absence of tapasin, a greater proportion of K b molecules that reach post-Golgi compartments (including the cell surface) may be poorly loaded and unstable.…”

Section: Alternate Mhc-i Ag Processing Involves Post-golgi Mhc-i Molementioning

confidence: 99%

“…Tapasin is complexed with calreticulin, MHC-I-␤ 2 -microglobulin, and TAP, and is necessary for association of TAP with the other components of this peptide loading complex (24,25). In addition to promoting assembly of the MHC-I peptide loading complex, tapasin has been suggested to help retain MHC-I molecules in the ER until they are loaded with high affinity peptides (25)(26)(27)(28)(29)(30)(31)(32). Recently, tapasin Ϫ/Ϫ mice were described (33,34).…”

Section: Onventional Class I Mhc (Mhc-i)mentioning

confidence: 99%

Tapasin−/− and TAP1−/− Macrophages Are Deficient in Vacuolar Alternate Class I MHC (MHC-I) Processing due to Decreased MHC-I Stability at Phagolysosomal pH

Chefalo

Grandea

Kaer

et al. 2003

The Journal of Immunology

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Alternate class I MHC (MHC-I) Ag processing via cytosolic or vacuolar pathways leads to cross-presentation of exogenous Ag to CD8 T cells. Vacuolar alternate MHC-I processing involves phagolysosomal Ag proteolysis and peptide binding to MHC-I in post-Golgi compartments. We report the first study of alternate MHC-I Ag processing in tapasin−/− cells and experiments with tapasin−/− and TAP1−/− macrophages that characterize alternate MHC-I processing. Tapasin promotes retention of MHC-I in the endoplasmic reticulum (ER) for loading with high affinity peptides, whereas tapasin−/− cells allow poorly loaded MHC-I molecules to exit the ER. Hypothetically, we considered that a large proportion of post-Golgi MHC-I on tapasin−/− cells might be peptide-receptive, enhancing alternate MHC-I processing. In contrast, alternate MHC-I processing was diminished in both tapasin−/− and TAP1−/− macrophages. Nonetheless, these cells efficiently presented exogenous peptide, suggesting a loss of MHC-I stability or function specific to vacuolar processing compartments. Tapasin−/− and TAP1−/− macrophages had decreased MHC-I stability and increased susceptibility of MHC-I to inactivation by acidic conditions (correlating with vacuolar pH). Incubation of tapasin−/− or TAP1−/− cells at 26°C decreased susceptibility of MHC-I to acid pH and reversed the deficiency in alternate MHC-I processing. Thus, tapasin and TAP are required for MHC-I to bind ER-derived stabilizing peptides to achieve the stability needed for alternate MHC-I processing via peptide exchange in acidic vacuolar processing compartments. Acidic pH destabilizes MHC-I, but also promotes peptide exchange, thereby enhancing alternate MHC-I Ag processing. These results are consistent with alternate MHC-I Ag processing mechanisms that involve binding of peptides to MHC-I within acidic vacuolar compartments.

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“…Tapasin bridges heavy chain-␤ 2 m heterodimers to TAP (Sadasivan et al, 1996) and thus provides physical proximity between MHC class I molecules and TAP. Tapasin also retains MHC class I molecules in the ER (Schoenhals et al, 1999;Barnden et al, 2000;Grandea et al, 2000), which might enhance peptide loading. In addition, tapasin optimizes the repertoire of bound peptides to achieve maximal affinity of the interaction (Garbi et al, 2000;Myers et al, 2000;Tan et al, 2002;Williams et al, 2002b;Howarth et al, 2004;Elliott and Williams, 2005).…”

mentioning

confidence: 99%

Redox-regulated Export of the Major Histocompatibility Complex Class I-Peptide Complexes from the Endoplasmic Reticulum

Lee

Park

Kang

et al. 2009

MBoC

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In contrast to the fairly well-characterized mechanism of assembly of MHC class I-peptide complexes, the disassembly mechanism by which peptide-loaded MHC class I molecules are released from the peptide-loading complex and exit the endoplasmic reticulum (ER) is poorly understood. Optimal peptide binding by MHC class I molecules is assumed to be sufficient for triggering exit of peptide-filled MHC class I molecules from the ER. We now show that protein disulfide isomerase (PDI) controls MHC class I disassembly by regulating dissociation of the tapasin-ERp57 disulfide conjugate. PDI acts as a peptide-dependent molecular switch; in the peptide-bound state, it binds to tapasin and ERp57 and induces dissociation of the tapasin-ERp57 conjugate. In the peptide-free state, PDI is incompetent to bind to tapasin or ERp57 and fails to dissociate the tapasin-ERp57 conjugates, resulting in ER retention of MHC class I molecules. Thus, our results indicate that even after optimal peptide loading, MHC class I disassembly does not occur by default but, rather, is a regulated process involving PDI-mediated interactions within the peptide-loading complex. INTRODUCTIONAssembly of major histocompatibility complex (MHC) class I molecules within the endoplasmic reticulum (ER) is essential for bringing antigenic peptides to CD8 ϩ T-cells, which scan and destroy the infected and transformed cells. MHC class I quality control ensures both the ER retention of suboptimally loaded MHC class I molecules and the release of those with a higher affinity to the cell surface. Therefore, the peptide-editing process for optimal peptide loading is critical for increasing the recognition by CD8 ϩ T-cells (Van Kaer, 2002;Cresswell, 2005).MHC class I assembly is a highly regulated process mediated by several ER-resident chaperones and accessory molecules (Cresswell, 2000;Williams et al., 2002a). After initial interaction with the lectin-like chaperone calnexin, MHC class I heavy chain-␤ 2 -microglobulin (␤ 2 m) heterodimers are incorporated into the peptide-loading complex (PLC), a multimolecular unit of ER proteins that promotes optimal peptide loading into MHC class I molecules (Hammerling et al., 1998;Pamer and Cresswell, 1998;Elliott and Williams, 2005). The PLC contains calreticulin, tapasin, transporters associated with antigen processing (TAP) and two thioldependent oxidoreductases, ERp57 and protein disulfide isomerase (PDI) (Garbi et al., 2005;Park et al., 2006;Santos et al., 2007).Several functions have been proposed for tapasin in facilitating optimal peptide loading and optimization of the peptide cargo (Grandea and Van Kaer, 2001;Purcell et al., 2001;Momburg and Tan, 2002). Tapasin bridges heavy chain-␤ 2 m heterodimers to TAP (Sadasivan et al., 1996) and thus provides physical proximity between MHC class I molecules and TAP. Tapasin also retains MHC class I molecules in the ER (Schoenhals et al., 1999;Barnden et al., 2000;Grandea et al., 2000), which might enhance peptide loading. In addition, tapasin optimizes the repertoire of bound pep...

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

Cited by 92 publications

References 53 publications

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

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

Tapasin−/− and TAP1−/− Macrophages Are Deficient in Vacuolar Alternate Class I MHC (MHC-I) Processing due to Decreased MHC-I Stability at Phagolysosomal pH

Redox-regulated Export of the Major Histocompatibility Complex Class I-Peptide Complexes from the Endoplasmic Reticulum

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