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

• DOI: 10.1038/s41467-024-52772-x
• Publication Date: 2024-10-01T17:01:59Z
• Authors: Michael L. van de...; Krishna Samanta; Nikita Sergejevs; LuLin Jiang; Maria Emilia Dueñas; Tiaan Heunis; Timothy Y. Huang; Randal J. Kaufman; Matthias Trost; Sumana Sanyal; Sally A. Cowley; Pedro Carvalho
• Keywords: Endoplasmic-reticulum-associated protein degradation; Antigen processing

AbstractImmune 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.