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.
Maksim V Baranov  1 ,  Frans Bianchi  2 ,  Anastasiya Schirmacher  3 ,  Melissa A C van Aart  1 ,  Sjors Maassen  2 ,  Elke M Muntjewerff  1 ,  Ilse Dingjan  1 ,  Martin Ter Beest  1 ,  Martijn Verdoes  1 ,  Samantha G L Keyser  4 ,  Carolyn R Bertozzi  5 ,  Ulf Diederichsen  3 ,  Geert van den Bogaart  6
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: [email protected].
PMID: 30612035 DOI: 10.1016/j.isci.2018.12.015
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.