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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)160-177
Number of pages18
JournaliScience
Volume11
Early online date20-Dec-2018
DOIs
Publication statusPublished - 25-Jan-2019

Keywords

  • MHC CLASS-II
  • ORAL INTERLEUKIN-12/23 INHIBITOR
  • CONTROLS PHAGOSOMAL PH
  • NADPH OXIDASE
  • DENDRITIC CELLS
  • CROSS-PRESENTATION
  • PHOSPHATIDYLINOSITOL 3,5-BISPHOSPHATE
  • LIPID KINASE
  • BINDING-SPECIFICITY
  • CYSTEINE PROTEASES

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