Why TAPBPR? Implications of an additional player in MHC class I peptide presentation

https://doi.org/10.1016/j.coi.2021.04.011Get rights and content

Highlights

  • Characterisation of TAPBPR has reveal new insights into MHC-I peptide editing.

  • Polymorphism in MHC-I alter their susceptibility to TAPBPR-mediated peptide editing.

  • Recent findings suggest TAPBPR functionality beyond classical MHC-I.

The peptide editor TAPBPR is the newest member of the major histocompatibility complex class I (MHC-I) antigen processing and presentation pathway. Since 2013, studies have explored the functions and mechanisms of action of this tapasin homolog. Here, we review the key insights gained from structural studies of the TAPBPR:MHC-I complex and the involvement of the TAPBPR loop in peptide exchange. However, despite recent advances, the question still remains: why do we need TAPBPR? The recent appreciation that different MHC-I allotypes vary in their ability to interact with TAPBPR, together with a role for TAPBPR in alternative presentation pathways highlights that much remains unknown concerning the biological need for TAPBPR.

Introduction

The essential function of major histocompatibility complex class I (MHC-I) as a recognition molecule for T-cell receptors relies mainly on the peptide repertoire presented. Illustrative to this fact is the intricate machinery involved in the loading and selection of the peptides onto MHC-I [1,2]. The transporters associated with antigen processing (TAP), together with the constituent parts of the peptide loading complex (PLC); ERp57, calreticulin and the peptide editor tapasin, have all been the subject of intense study [2,3].

In 2002, Teng et al. described a tapasin-like gene called ‘TAPBPR’, for TAP binding protein (aka tapasin) related, that encoded a protein with 22% sequence homology to tapasin [4]. In 2013, TAPBPR was found to bind to MHC-I/β2m heterodimers outside of the PLC in the ER and the Golgi [5]. Subsequently, the binding of TAPBPR and tapasin to MHC-I was found to be mutually exclusive [6]. Indeed, TAPBPR and tapasin bind to the same face of MHC-I, the residues required for binding to MHC-I are conserved across the two homologs, and mutations in MHC-I which abrogate binding to tapasin also abolish binding to TAPBPR [6]. Thus, despite the relatively low sequence homology between TAPBPR and tapasin, critical residues show a high degree of conservation.

A few years later, studies revealed that TAPBPR functioned as a peptide editor on MHC-I [7,8] (Figure 1). Furthermore, depletion or overexpression of TAPBPR impacted the size of the presented peptide repertoire and the proportion of peptides which contained canonical anchor residues [8]. In addition to its function as a peptide editor, TAPBPR was also shown to play a role in MHC-I quality control; TAPBPR was shown to interact with UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1) to promote the reglucosylation of the glycan on peptide-receptive MHC-I, promoting its recognition by calreticulin and recruitment back into the PLC [9]. Together, this body of work established TAPBPR as a legitimate component of the MHC-I antigen processing and presentation pathway.

Section snippets

Structural studies of the TAPBPR:MHC-I complex reveal conformational changes central to the mechanism of peptide editing

Two structural characterizations of TAPBPR in complex with MHC-I were published simultaneously in 2017 [10,11]. As well as confirming that the binding of TAPBPR to MHC-I was similar to that of tapasin-MHC-I binding [6,12], the structures implicated key conformational changes in MHC-I central to the process of peptide editing. Both structures revealed that TAPBPR widens the peptide-binding groove of MHC-I and demonstrated conformational change at the MHC-I F-pocket in the process of peptide

A role for the TAPBPR loop in peptide editing?

A significant discrepancy between the two published structures is that one suggests that a loop of TAPBPR protrudes into the F-pocket of the MHC-I peptide-binding groove [10], whereas the other does not [11]. While the structural data underpinning the modelling of the loop may be contentious [14], it hinted that the loop might play a role in the process of TAPBPR-mediated peptide editing [10]. Indeed, further functional evidence has implicated the involvement of the K22-D35 loop of TAPBPR (aka

Why do we need TAPBPR?

Despite the immense progress recently made identifying TAPBPR as a second peptide editor for MHC-I and the significant structural insight gained regarding how it performs this function, the fundamental question still remains: why do we need TAPBPR? Curiously, while MHC-II appears to require only one peptide editor, DM, (which is subjected to regulation by DO in some cell types) to mediate peptide selection [20, 21, 22, 23, 24], MHC-I appears to require two distinct peptide editing steps, one

Conclusions

While there has been a flurry of investigation into TAPBPR in the last six years, resulting in a significant enhancement in our understanding into the process of peptide editing on MHC-I, the question remains: why do we need TAPBPR? Despite TAPBPR functioning as a peptide editor in a complex pathway associated with susceptibility to and protection against many diseases [40,41], there is still much to learn about TAPBPR and its overall role in the immune system.

Conflict of interest statement

Nothing declared.

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

This work was supported by Wellcome [grant numbers 220012/Z/19/Z and 219479/Z/19/Z] and Cancer Research UK [grant number A25343]. We thank Dr Alice Abreu Torres and Dr Arwen Altenburg (University of Cambridge, UK) for helpful discussions.

References (41)

  • J.S. Blum et al.

    Pathways of antigen processing

    Annu Rev Immunol

    (2013)
  • A. Blees et al.

    Structure of the human MHC-I peptide-loading complex

    Nature

    (2017)
  • M.S. Teng et al.

    A human TAPBP (TAPASIN)-related gene, TAPBP-R

    Eur J Immunol

    (2002)
  • L.H. Boyle et al.

    Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway

    Proc Natl Acad Sci U S A

    (2013)
  • C. Hermann et al.

    The binding of TAPBPR and Tapasin to MHC class I is mutually exclusive

    J Immunol

    (2013)
  • G.I. Morozov et al.

    Interaction of TAPBPR, a tapasin homolog, with MHC-I molecules promotes peptide editing

    Proc Natl Acad Sci U S A

    (2016)
  • C. Hermann et al.

    TAPBPR alters MHC class I peptide presentation by functioning as a peptide exchange catalyst

    eLife

    (2015)
  • A. Neerincx et al.

    TAPBPR bridges UDP-glucose:glycoprotein glucosyltransferase 1 onto MHC class I to provide quality control in the antigen presentation pathway

    eLife

    (2017)
  • C. Thomas et al.

    Structure of the TAPBPR-MHC I complex defines the mechanism of peptide loading and editing

    Science

    (2017)
  • J. Jiang et al.

    Crystal structure of a TAPBPR-MHC I complex reveals the mechanism of peptide editing in antigen presentation

    Science

    (2017)
  • Cited by (9)

    • Rapid peptide exchange on MHC class I by small molecules elucidates dynamics of bound peptide

      2022, Current Research in Immunology
      Citation Excerpt :

      This suggests an at least partial complementarity in the molecular mechanism. Peptide exchange on MHC-I can be achieved by several methods (UV cleavage of peptides (Rodenko et al., 2006), temperatures (Luimstra et al., 2019), dipeptides (Saini et al., 2015), and tapasin (Praveen et al., 2010; Sadasivan et al., 1996) or TAPBPR (Hafstrand et al., 2021; Hermann et al., 2015; Overall et al., 2020). Here, we have found that ethanol and methanol, but no larger alcohols nor other hydrogen bond donors, can exchange peptides on A2 and A24.

    View all citing articles on Scopus
    3

    Contributed equally.

    View full text