Tapasin assembly surveillance by the RNF185/Membralin ubiquitin ligase complex regulates MHC-I surface expression
Summary
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).
| Authors | 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 |
|---|---|
| Journal | Nature communications |
| Publication Date | 2024 Oct 1;15(1):8508 |
| PubMed | 39353943 |
| PubMed Central | PMC11445256 |
| DOI | 10.1038/s41467-024-52772-x |