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

• Published in: iScience Vol. 11; pp. 160 - 177
• Main Authors: Baranov, Maksim V., Bianchi, Frans, Schirmacher, Anastasiya, van Aart, Melissa A.C., Maassen, Sjors, Muntjewerff, Elke M., Dingjan, Ilse, ter Beest, Martin, Verdoes, Martijn, Keyser, Samantha G.L., Bertozzi, Carolyn R., Diederichsen, Ulf, van den Bogaart, Geert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.01.2019; Elsevier
• Subjects: Immune Response; Immunology; Molecular Mechanism of Gene Regulation; Molecular Mechanism of Gene Regulation; Immune Response; Immunology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2018.12.015

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. [Display omitted] •PIKfyve converts PI(3)P into PI(3,5)P2 on the surface of endosomes and phagosomes•PIKfyve of DCs modulates phagosomal maturation, acidification, and ROS production•PIKfyve defects disrupt cathepsin S trafficking and activity•Inactive cathepin S slows Ii processing for MHC class II trafficking and antigen loading Molecular Mechanism of Gene Regulation; Immunology; Immune Response