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

Autor: van de Weijer ML; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK., Samanta K; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK., Sergejevs N; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK., Jiang L; Degenerative Diseases Program, Genetics, and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.; Altos Labs-Bay Institute of Science, Redwood City, CA, USA., Dueñas ME; Biosciences Institute, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.; Telethon Kids Institute, Perth, Nedlands, WA, 6009, Australia., Heunis T; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.; Immunocore Ltd, 92 Park Drive, Abingdon, OX14 4RY, UK., Huang TY; Degenerative Diseases Program, Genetics, and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Kaufman RJ; Degenerative Diseases Program, Genetics, and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Trost M; Biosciences Institute, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Sanyal S; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK., Cowley SA; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.; James and Lillian Martin Centre for Stem Cell Research, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Carvalho P; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK. pedro.carvalho@path.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Oct 01; Vol. 15 (1), pp. 8508. Date of Electronic Publication: 2024 Oct 01.
DOI: 10.1038/s41467-024-52772-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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