The ER folding sensor UGGT1 acts on TAPBPR-chaperoned peptide-free MHC I
Abstract
Adaptive immune responses are triggered by antigenic peptides presented on major histocompatibility complex class I (MHC I) at the surface of pathogen-infected or cancerous cells. Formation of stable peptide-MHC I complexes is facilitated by tapasin and TAPBPR, two related MHC I-specific chaperones that catalyze selective loading of suitable peptides onto MHC I in a process called peptide editing or proofreading. On their journey to the cell surface, MHC I complexes must pass a quality control step performed by UGGT1, which senses the folding status of the transiting N-linked glycoproteins in the endoplasmic reticulum (ER). UGGT1 reglucosylates non-native glycoproteins and thereby allows them to revisit the ER folding machinery. Here, we describe a reconstituted in-vitro system of purified human proteins that enabled us to delineate the function of TAPBPR during the UGGT1-catalyzed quality control and reglucosylation of MHC I. By combining glycoengineering with liquid chromatography-mass spectrometry, we show that TAPBPR promotes reglucosylation of peptide-free MHC I by UGGT1. Thus, UGGT1 cooperates with TAPBPR in fulfilling a crucial function in the quality control mechanisms of antigen processing and presentation.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; a Source Data file for Figures 1C and D, Figure 2, Figure 3B-F, Figure 4B,C, E, and F as well as Figure 1-figure supplement 1 and 2, Figure 2-figure supplement 1 and Figure 3-figure supplement 1.
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Author details
Funding
Deutsche Forschungsgemeinschaft (TA 157/12-1)
- Robert Tampé
Deutsche Forschungsgemeinschaft (CRC 1507/P18)
- Robert Tampé
European Research Council (798121)
- Robert Tampé
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Sagert et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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