2019
DOI: 10.1016/j.isci.2018.12.015
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The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation

Abstract: SummaryAntigen 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 c… Show more

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Cited by 42 publications
(52 citation statements)
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References 122 publications
(242 reference statements)
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“…1,13 The small molecule, apilimod, directly inhibits the kinase activity of PIKfyve 22 in concentrations ranging from 1 to 1000 nM. 12,17 When apilimod was tested as an antiproliferative agent, it had an IC50 of 20 nM and a dissociation constant (Kd) of 75 pM 12,22 It has also been shown that PIKfyve is of critical importance in the lysosomal biogenesis and homeostasis in platelets. 23 F I G U R E 2 PIKfyve and Snx10 colocalize in osteoclasts and gastric zymogenic cells.…”
Section: Discussionmentioning
confidence: 99%
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“…1,13 The small molecule, apilimod, directly inhibits the kinase activity of PIKfyve 22 in concentrations ranging from 1 to 1000 nM. 12,17 When apilimod was tested as an antiproliferative agent, it had an IC50 of 20 nM and a dissociation constant (Kd) of 75 pM 12,22 It has also been shown that PIKfyve is of critical importance in the lysosomal biogenesis and homeostasis in platelets. 23 F I G U R E 2 PIKfyve and Snx10 colocalize in osteoclasts and gastric zymogenic cells.…”
Section: Discussionmentioning
confidence: 99%
“…PIKfyve has multiple roles, for example, in the conversion of early endo/ phagosomes into mature lysosomes, lysosomal acidification, trafficking to late endosomes/lysosomes, and interleukin-12 secretion in monocyte-derived dendritic cells. In addition, this kinase plays a key role in T-cell activation and in metastasis, and it has emerged as a potential target for treating solid tumors because it promotes cancer cell migration and invasion [16][17][18][19] In the present report, we studied the potential of PIKfyve and its inhibitor apilimod to mediate osteoclast differentiation and activity, thereby identifying this as a possible therapeutic strategy to mediate bone loss.…”
Section: Introductionmentioning
confidence: 99%
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“…More recently, PIKfyve was shown to be critical for maturation of phagocytic compartments in dendritic cells and generation of an "MHC Class II compartment" where protein fragments are combined with MHC Class II molecules for antigen presentation. Inhibition of PIKfyve in dendritic cells impaired lysosomal acidification and antigen presentation, slowing maturation of the phagocytic compartment and reducing the activity of proteases with an acidic pH optimum (Baranov et al, 2019). In a Dictyostelium model of phagocytosis, loss of PI(3,5)P 2 decreased acidification and increased survival time of Legionella bacteria (Buckley et al, 2019).…”
Section: Phagocytosis and Immunitymentioning
confidence: 99%
“…It has been studied in humans in several clinical trials and been found to be safe and well tolerated. A theoretical concern with the use of apilimod for treating viral infections, however, is that it may interfere with T cell antigen presentation (23). Apilimod is being studied for the treatment of mild SARS-CoV-2 infections in one randomized placebocontrolled Phase II trial.…”
Section: Host-acting Compoundsmentioning
confidence: 99%