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Tapasin assembly surveillance by the RNF185/Membralin ubiquitin ligase complex regulates MHC-I surface expression

Lookup NU author(s): Dr Maria Duenas FadicORCiD, Professor Matthias TrostORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© The Author(s) 2024.Immune surveillance by cytotoxic T cells eliminates tumor cells and cells infected by intracellular pathogens. This process relies on the presentation of antigenic peptides by Major Histocompatibility Complex class I (MHC-I) at the cell surface. The loading of these peptides onto MHC-I depends on the peptide loading complex (PLC) at the endoplasmic reticulum (ER). Here, we uncovered that MHC-I antigen presentation is regulated by ER-associated degradation (ERAD), a protein quality control process essential to clear misfolded and unassembled proteins. An unbiased proteomics screen identified the PLC component Tapasin, essential for peptide loading onto MHC-I, as a substrate of the RNF185/Membralin ERAD complex. Loss of RNF185/Membralin resulted in elevated Tapasin steady state levels and increased MHC-I at the surface of professional antigen presenting cells. We further show that RNF185/Membralin ERAD complex recognizes unassembled Tapasin and limits its incorporation into PLC. These findings establish a novel mechanism controlling antigen presentation and suggest RNF185/Membralin as a potential therapeutic target to modulate immune surveillance.

Publication metadata

Author(s): van de Weijer ML, Samanta K, Sergejevs N, Jiang L, Dueñas ME, Heunis T, Huang TY, Kaufman RJ, Trost M, Sanyal S, Cowley SA, Carvalho P

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2024

Volume: 15

Issue: 1

Online publication date: 01/10/2024

Acceptance date: 19/09/2024

Date deposited: 23/10/2024

ISSN (electronic): 2041-1723

Publisher: Nature Research

URL: https://doi.org/10.1038/s41467-024-52772-x

DOI: 10.1038/s41467-024-52772-x

Data Access Statement: The raw proteomics dataset generated during this study is available at PRIDE as PXD048728. The western blotting data generated during this study are available at Mendeley Data (https://doi.org/10.17632/vfd47jgr8t). Source data are provided in this paper.

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