Retention of empty MHC class I molecules by tapasin is essential to reconstitute antigen presentation in invertebrate cells

Schoenhals, Gary J.; Krishna, Raman Murli; Grandea, Andres G.; Spies, Thomas A.; Peterson, Per A.; Yang, Young Mok; Früh, Klaus

doi:10.1093/emboj/18.3.743

Cited by 112 publications

(107 citation statements)

References 60 publications

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“…This indicates that in the absence of tapasin K b molecules exit the ER more rapidly, and it suggests that tapasin plays a role in ER retention of K b molecules. Our observation in human APC is consistent with observations of tapasin-mediated retention of murine H-2 molecules in reconstituted insect cells (10). To achieve equivalent surface K b levels, the tapasin-deficient K b .220 cells appear to biosynthesize greater quantities of H-2K b compared with K b .220.hTsn cells (2-to 5-fold; Fig.…”

Section: High-level Surface Expression Of H-2k B Class I Molecules Onsupporting

confidence: 90%

“…This suggests that tapasin increases overall peptide transport from the cytosol into the lumen of the ER, but it does not appear to affect the rate of peptide translocation (8). In addition, tapasin retains class I molecules that fail to bind peptide in the ER of insect cells (10) and may also be involved in the retention of peptide-bound class I molecules during a peptide optimization step in mammalian cells (11,12). Paradoxically, most class I molecules expressed in human cells lacking functional tapasin are retained in the ER and are inefficiently expressed at the cell surface (4,7,9,(13)(14)(15)(16).…”

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confidence: 99%

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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: High-level Surface Expression Of H-2k B Class I Molecules Onsupporting

confidence: 90%

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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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“…MHC I molecules are retained in the ER by the specific chaperone tapasin until they acquire high affinity peptides (30). Therefore, the retention of MHC I in the ER could be the result of a lack in peptide loading, as observed for viruses that inhibit the peptide import by TAP (16,17).…”

Section: Cpv Infection Does Not Affect the Thermostability Of Mhc Imentioning

confidence: 99%

Cowpox Virus Evades CTL Recognition and Inhibits the Intracellular Transport of MHC Class I Molecules

Dasgupta

Hammarlund

Slifka

et al. 2007

The Journal of Immunology

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Orthopoxviruses evade host immune responses by using a number of strategies, including decoy chemokine receptors, regulation of apoptosis, and evasion of complement-mediated lysis. Different from other poxviral subfamilies, however, orthopoxviruses are not known to evade recognition by CTL. In fact, vaccinia virus (VV) is used as a vaccine against smallpox and a vector for eliciting strong T cell responses to foreign Ags. and both human and mouse T cells are readily stimulated by VV-infected APC in vitro. Surprisingly, however, CD8+ T cells of mice infected with cowpox virus (CPV) or VV recognized APC infected with VV but not APC infected with CPV. Likewise, CD8+ T cells from vaccinated human subjects could not be activated by CPV-infected targets and CPV prevented the recognition of VV-infected APC upon coinfection. Because CD8+ T cells recognize viral peptides presented by MHC class I (MHC I), we examined surface expression, total levels, and intracellular maturation of MHC I in CPV- and VV-infected human and mouse cells. Although total levels of MHC I were unchanged, CPV reduced surface levels and inhibited the intracellular transport of MHC I early during infection. CPV did not prevent peptide loading of MHC I but completely inhibited MHC I exit from the endoplasmic reticulum. Because this inhibition was independent of viral replication, we conclude that an early gene product of CPV abrogates MHC I trafficking, thus rendering CPV-infected cells “invisible” to T cells. The absence of this immune evasion mechanism in VV likely limits virulence without compromising immunogenicity.

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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).…”

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confidence: 99%

“…MHC class I molecules associating with poorly with TAP and tapasin are exported more rapidly from the ER than are the MHC class I molecules efficiently associate with TAP and tapasin (Neefjes and Ploegh, 1988;Neisig et al, 1996). In addition, the function of tapasin has been proposed to retain empty MHC class I molecules in the ER (Schoenhals et al, 1999;Grandea et al, 2000). These individual observations can be explained by a function of the ERp57-tapasin conjugate in retaining MHC class I molecules in the ER and argue that impaired function of the tapasin-ERp57 conjugate results in a loss of stringency in quality control of MHC class I molecules.…”

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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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Retention of empty MHC class I molecules by tapasin is essential to reconstitute antigen presentation in invertebrate cells

Cited by 112 publications

References 60 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

Cowpox Virus Evades CTL Recognition and Inhibits the Intracellular Transport of MHC Class I Molecules

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

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