The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation

Maksim V Baranov; Frans Bianchi; Anastasiya Schirmacher; Melissa A C van Aart; Sjors Maassen; Elke M Muntjewerff; Ilse Dingjan; Martin Ter Beest; Martijn Verdoes; Samantha G L Keyser; Carolyn R Bertozzi; Ulf Diederichsen; Geert van den Bogaart

doi:10.1016/j.isci.2018.12.015

The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation

iScience. 2019 Jan 25:11:160-177. doi: 10.1016/j.isci.2018.12.015. Epub 2018 Dec 20.

Affiliations

¹ Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands.
² Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands; Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, Groningen 9747 AG, the Netherlands.
³ Institute of Organic and Biomolecular Chemistry, Georg-August-University of Göttingen, Tammannstr. 2, 37077 Göttingen, Germany.
⁴ Department of Chemistry, University of California, Berkeley, CA 94720, USA.
⁵ Department of Chemistry and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
⁶ Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands; Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, Groningen 9747 AG, the Netherlands. Electronic address: g.van.den.bogaart@rug.nl.

Abstract

Antigen presentation to T cells in major histocompatibility complex class II (MHC class II) requires the conversion of early endo/phagosomes into lysosomes by a process called maturation. Maturation is driven by the phosphoinositide kinase PIKfyve. Blocking PIKfyve activity by small molecule inhibitors caused a delay in the conversion of phagosomes into lysosomes and in phagosomal acidification, whereas production of reactive oxygen species (ROS) increased. Elevated ROS resulted in reduced activity of cathepsin S and B, but not X, causing a proteolytic defect of MHC class II chaperone invariant chain Ii processing. We developed a novel universal MHC class II presentation assay based on a bio-orthogonal "clickable" antigen and showed that MHC class II presentation was disrupted by the inhibition of PIKfyve, which in turn resulted in reduced activation of CD4⁺ T cells. Our results demonstrate a key role of PIKfyve in the processing and presentation of antigens, which should be taken into consideration when targeting PIKfyve in autoimmune disease and cancer.

Keywords: Immune Response; Immunology; Molecular Mechanism of Gene Regulation.

Grants and funding

R37 GM058867/GM/NIGMS NIH HHS/United States