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Tapasin assembly surveillance by the RNF185/Membralin ubiquitin ligase complex regulates MHC-I surface expression.
Michael L van de Weijer1, Krishna Samanta1, Nikita Sergejevs1
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
Nature Communications
|October 1, 2024
Summary
The RNF185/Membralin ER-associated degradation (ERAD) complex regulates immune surveillance by controlling Tapasin levels, impacting Major Histocompatibility Complex class I (MHC-I) presentation. This discovery offers a new therapeutic target for modulating immune responses.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Immune surveillance relies on cytotoxic T cells eliminating threats via Major Histocompatibility Complex class I (MHC-I) antigen presentation.
- Peptide loading onto MHC-I occurs at the endoplasmic reticulum (ER) via the peptide loading complex (PLC).
- ER-associated degradation (ERAD) is a critical protein quality control pathway in the ER.
Purpose of the Study:
- To investigate the role of ERAD in regulating MHC-I antigen presentation.
- To identify novel regulators of the peptide loading complex (PLC).
Main Methods:
- Unbiased proteomics screen to identify PLC components as ERAD substrates.
- Analysis of Tapasin and MHC-I levels in cells with and without RNF185/Membralin.
- Biochemical assays to determine RNF185/Membralin ERAD complex interaction with Tapasin.
Main Results:
- Tapasin, a key PLC component, was identified as a substrate of the RNF185/Membralin ERAD complex.
- Loss of RNF185/Membralin led to increased Tapasin levels and enhanced surface MHC-I expression.
- The RNF185/Membralin ERAD complex specifically targets unassembled Tapasin, limiting its incorporation into the PLC.
Conclusions:
- ERAD, via the RNF185/Membralin complex, acts as a novel regulator of MHC-I antigen presentation.
- This mechanism controls the availability of Tapasin for peptide loading.
- RNF185/Membralin presents a potential therapeutic target for enhancing immune surveillance.
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