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bioRxiv · 10.1101/2023.01.08.523166

The ER folding sensor UGGT1 acts on TAPBPR-chaperoned peptide-free MHC I

Sagert, L.·Winter, C.·Ruppert, I.·Zehetmaier, M.·Thomas, C.·Tampe, R.
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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.

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Sagert, L., Winter, C., Ruppert, I., Zehetmaier, M., Thomas, C., Tampe, R.. 2023-01-10. The ER folding sensor UGGT1 acts on TAPBPR-chaperoned peptide-free MHC I. https://doi.org/10.1101/2023.01.08.523166

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