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

Michael L. Weijer, Krishna Samanta, Nikita Sergejevs, LuLin Jiang, Maria Emilia Dueñas, Tiaan Heunis, Timothy Y. Huang, Randal J. Kaufman, Matthias Trost, Sumana Sanyal, Sally A. Cowley and Pedro Carvalho ()
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Michael L. Weijer: University of Oxford
Krishna Samanta: University of Oxford
Nikita Sergejevs: University of Oxford
LuLin Jiang: Sanford Burnham Prebys Medical Discovery Institute
Maria Emilia Dueñas: Newcastle University
Tiaan Heunis: University of Oxford
Timothy Y. Huang: Sanford Burnham Prebys Medical Discovery Institute
Randal J. Kaufman: Sanford Burnham Prebys Medical Discovery Institute
Matthias Trost: Newcastle University
Sumana Sanyal: University of Oxford
Sally A. Cowley: University of Oxford
Pedro Carvalho: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52772-x

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