Dynamic interactome of the MHC I peptide loading complex in human dendritic cells

Author:

Barends Martina1,Koller Nicole1,Schölz Christian2ORCID,Durán Verónica3,Bošnjak Berislav4ORCID,Becker Jennifer3,Döring Marius3ORCID,Blees Hanna1,Förster Reinhold45,Kalinke Ulrich35ORCID,Tampé Robert1ORCID

Affiliation:

1. Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany

2. Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, Ludwig-Maximilians-Universität München, 80336 Munich, Germany

3. Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany

4. Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany

5. Cluster of Excellence (EXC 2155) – Resolving Infection Susceptibility, Hannover Medical School, 30625 Hannover, Germany

Abstract

Dendritic cells (DCs) orchestrate immune responses by presenting antigenic peptides on major histocompatibility complex (MHC) molecules to T cells. Antigen processing and presentation via MHC I rely on the peptide-loading complex (PLC), a supramolecular machinery assembled around the transporter associated with antigen processing (TAP), which is the peptide transporter in the endoplasmic reticulum (ER) membrane. We studied antigen presentation in human DCs by isolating monocytes from blood and differentiating them into immature and mature DCs. We uncovered that during DC differentiation and maturation, additional proteins are recruited to the PLC, including B-cell receptor-associated protein 31 (BAP31), vesicle-associated membrane protein-associated protein A (VAPA), and extended synaptotagmin-1 (ESYT1). We demonstrated that these ER cargo export and contact site–tethering proteins colocalize with TAP and are within 40 nm proximity of the PLC, suggesting that the antigen processing machinery is located near ER exit- and membrane contact sites. While CRISPR/Cas9-mediated deletion of TAP and tapasin significantly reduced MHC I surface expression, single-gene deletions of the identified PLC interaction partners revealed a redundant role of BAP31, VAPA, and ESYT1 in MHC I antigen processing in DCs. These data highlight the dynamics and plasticity of PLC composition in DCs that previously was not recognized by the analysis of cell lines.

Funder

Deutsche Forschungsgemeinschaft

Bundesministerium für Bildung und Forschung

EC | ERC | HORIZON EUROPE European Research Council

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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