Nature Communications (Oct 2024)

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

  • Michael L. van de 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,
  • Pedro Carvalho

DOI
https://doi.org/10.1038/s41467-024-52772-x
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 14

Abstract

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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.