The quality control of MHC class I peptide loading

https://doi.org/10.1016/j.ceb.2008.09.005Get rights and content

The assembly of major histocompatibility complex (MHC) class I molecules is one of the more widely studied examples of protein folding in the endoplasmic reticulum (ER). It is also one of the most unusual cases of glycoprotein quality control involving the thiol oxidoreductase ERp57 and the lectin-like chaperones calnexin and calreticulin. The multistep assembly of MHC class I heavy chain with β2-microglobulin and peptide is facilitated by these ER-resident proteins and further tailored by the involvement of a peptide transporter, aminopeptidases, and the chaperone-like molecule tapasin. Here we summarize recent progress in understanding the roles of these general and class I-specific ER proteins in facilitating the optimal assembly of MHC class I molecules with high affinity peptides for antigen presentation.

Introduction

The major histocompatibility complex (MHC) class I heavy chain (HC) was one of the first chaperone substrates to be identified in the early 1990s and since then its assembly with β2-microglobulin and peptide has been a popular model system for studying endoplasmic reticulum (ER) folding pathways. Loading MHC class I molecules with peptide ligands, however, poses an unusual challenge for the ER quality control machinery. MHC class I molecules display a ‘peptide fingerprint’ of intracellular protein content to CD8+ T cells for immune surveillance of viruses and tumors. This requires diversity of the peptide repertoire as well as stable association so that the class I-peptide complexes survive trafficking and prolonged expression at the cell surface where the encounter with T cells occurs. A specialized pathway for MHC class I assembly has evolved that overcomes these apparently contradictory principles of degeneracy and high affinity.

Peptide loading of MHC class I molecules is the final event in a multistep assembly pathway that is an adaptation of a quality control cycle that regulates the folding of conventional glycoproteins [1]. This system involves the lectin-like chaperones calnexin (CNX) and calreticulin (CRT), which transiently bind to newly synthesized proteins bearing monoglucosylated N-linked glycans and promote their folding (Figure 1a) [2]. These chaperones also recruit the thiol oxidoreductase ERp57, which isomerizes disulfide bonds to facilitate acquisition of the correct conformation by the glycoprotein. Deglucosylation of the substrate by glucosidase II is coordinated with its release from CNX/CRT, and its folding status is assessed by the enzyme UDP-glucose glycoprotein transferase (UGT). This enzyme reglucosylates the glycan only if the glycoprotein remains incorrectly folded, allowing its re-entry into the quality control cycle.

The ER quality control machinery facilitates two discrete stages of MHC class I assembly (Figure 1b) [1]. Interactions with CNX and ERp57 are thought to mediate the early folding events of the MHC class I HC. After β2m association the class I heterodimer is rapidly recruited into the peptide loading complex (PLC), which consists of the transporter associated with antigen processing (TAP), the MHC class I-specific chaperone tapasin, CRT, and ERp57. Peptides are generated in the cytosol by the proteasome, shuttled into the ER by TAP, and trimmed by aminopeptidases to 8–10 AA, a length appropriate for MHC class I association. Binding of high affinity peptides induces the release of MHC class I-peptide complexes that traffic to the cell surface. In this review we focus on the final events responsible for the optimal loading of MHC class I molecules.

Section snippets

Tapasin and the PLC: ‘specialized quality control’

The involvement of tapasin dramatically changes the dynamics of the typically weak and transient interactions observed between CRT, ERp57, and their glycoprotein substrates [2] as the association of many MHC class I alleles with the PLC is quite stable and prolonged [3, 4]. Studies of tapasin-deficient cells have indicated that the CRT/ERp57 system by itself cannot promote optimal MHC class I assembly [5, 6] and tapasin function is compromised in the absence of CRT or ERp57 [7, 8••]. How the

ERp57 and redox reactions in MHC class I assembly and peptide loading

To address the role of ERp57 in the PLC, Garbi et al. made a conditional knockout of ERp57 in mouse B cells [8••]. Total and cell surface MHC class I (H2-Kb) were reduced by ∼50% compared to wild-type B cells. MHC class I molecules were transported more rapidly from the ER and had a decreased half-life at the cell surface, suggesting poor peptide binding. In addition, antigen presentation was reduced when peptide supply was limited. A less dramatic phenotype was observed when siRNA was used to

Mechanism of MHC class I peptide loading

The primary role of tapasin is to stabilize empty MHC class I molecules and promote the binding of high affinity peptides, a process known as ‘peptide editing’ [31, 35, 36]. Experimental approaches involving intact cells, while supporting this idea, are limited in helping us understand the mechanism of PLC activity. Surface expression and thermostability of MHC class I molecules is commonly used as a surrogate for measuring the affinity of bound peptides, but can be complicated by post-ER

Peptide processing in the ER

The assembly of MHC class I molecules is further facilitated by ER aminopeptidases that favor the generation of suitable peptides. Many of the peptides transported by TAP are longer than the 8–10 residues suitable for MHC class I binding. Although the appropriate C-termini of the transported peptides are generated in the cytosol, the N-termini can be extended. In 2002 a soluble interferon-γ-inducible ER aminopeptidase, named ERAAP in mice and ERAP1 in humans, was isolated [42, 43, 44]. Recent

Concluding remarks

The assembly of MHC class I molecules involves general and specific mechanisms and thus represents a unique case of ER quality control. The early stages of MHC class I HC folding proceed in a conventional manner, but the involvement of tapasin, TAP, and ER aminopeptidases with CRT and ERp57 customizes the quality control machinery to ensure that MHC class I molecules preferentially bind high affinity peptides. Although considerable progress has been made in understanding MHC class I assembly,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to our colleagues if their papers are not mentioned; citations and discussions were limited owing to space constraints. The authors would like to thank Drs David Peaper and Ralf Leonhardt for helpful discussions. PAW and PC are supported by the Howard Hughes Medical Institute.

References (55)

  • H.G. Ljunggren et al.

    Empty class I molecules come out in the cold

    Nature

    (1990)
  • R. Olson et al.

    Structure of a pheromone receptor-associated MHC molecule with an open and empty groove

    PLoS Biol

    (2005)
  • G.E. Hammer et al.

    The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules

    Nat Immunol

    (2006)
  • G.E. Hammer et al.

    In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides

    Nat Immunol

    (2007)
  • D.R. Peaper et al.

    Regulation of MHC class I assembly and Peptide binding

    Annu Rev Cell Dev Biol

    (2008)
  • A. Helenius et al.

    Roles of N-linked glycans in the endoplasmic reticulum

    Annu Rev Biochem

    (2004)
  • B. Ortmann et al.

    A critical role for tapasin in the assembly and function of multimeric MHC class I–TAP complexes

    Science

    (1997)
  • N. Garbi et al.

    Impaired immune responses and altered peptide repertoire in tapasin-deficient mice

    Nat Immunol

    (2000)
  • N. Garbi et al.

    Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57

    Nat Immunol

    (2006)
  • N. Garbi et al.

    A major role for tapasin as a stabilizer of the TAP peptide transporter and consequences for MHC class I expression

    Eur J Immunol

    (2003)
  • R.M. Leonhardt et al.

    Critical role for the tapasin-docking site of TAP2 in the functional integrity of the MHC class I-peptide-loading complex

    J Immunol

    (2005)
  • E. Procko et al.

    Identification of domain boundaries within the N-termini of TAP1 and TAP2 and their importance in tapasin binding and tapasin-mediated increase in peptide loading of MHC class I

    Immunol Cell Biol

    (2005)
  • J. Koch et al.

    The first N-terminal transmembrane helix of each subunit of the antigenic peptide transporter TAP is essential for independent tapasin binding

    FEBS Lett

    (2006)
  • T.P. Dick et al.

    Disulfide bond isomerization and the assembly of MHC class I-peptide complexes

    Immunity

    (2002)
  • C.E. Jessop et al.

    ERp57 is essential for efficient folding of glycoproteins sharing common structural domains

    EMBO J

    (2007)
  • D.R. Peaper et al.

    The redox activity of ERp57 is not essential for its functions in MHC class I peptide loading

    Proc Natl Acad Sci U S A

    (2008)
  • E.-M. Frickel et al.

    TROSY-NMR reveals interaction between ERp57 and the tip of the calreticulin P-domain

    Proc Natl Acad Sci U S A

    (2002)

    • Cited by (167)

    • Bulk RNA sequencing reveals the comprehensive genetic characteristics of human cord blood-derived natural killer cells

      2024, Regenerative Therapy

    • The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent

      2023, Cell Reports

    • Get into the groove! The influence of TAPBPR on cargo selection

      2023, Current Opinion in Immunology

    • TAP-ing into the cross-presentation secrets of dendritic cells

      2023, Current Opinion in Immunology

    • Antibodies to calnexin and mutated calreticulin are common in human sera

      2023, Current Research in Translational Medicine

    • Critical roles of protein disulfide isomerases in balancing proteostasis in the nervous system

      2022, Journal of Biological Chemistry
    View all citing articles on Scopus
    View full text
    Copyright © 2008 Elsevier Ltd. All rights reserved.