1-phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) (PIKfyve)

1-phosphatidylinositol 3-phosphate 5-kinase, commonly known as PIKfyve, is a large multidomain lipid kinase that plays a central role in the endolysosomal system (UniProt Q9Y2I7). It primarily catalyzes the phosphorylation of phosphatidylinositol 3-phosphate (PI3P) to generate phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), and it is also involved in the production of phosphatidylinositol 5-phosphate (PI5P) (PubMed: 10419465, 22621786). These rare phosphoinositides are critical for maintaining endosomal morphology, regulating lysosomal acidification, and facilitating membrane trafficking and autophagy (PubMed: 25178411, 31427458). Dysregulation of PIKfyve is linked to various conditions, including neurodegenerative diseases like ALS, certain cancers such as multiple myeloma and pancreatic ductal adenocarcinoma, and viral infections including COVID-19 and Ebola, where it facilitates viral entry (PubMed: 32697944, ashpublications.org). Pharmacological inhibition of PIKfyve, notably by the small molecule apilimod (LAM-002), leads to characteristic cytoplasmic vacuolation and disruption of autophagic flux, making it a promising therapeutic target for inducing non-apoptotic cell death in tumors and blocking viral replication (nih.gov, acs.org). The enzyme also possesses serine-protein kinase activity, allowing for autophosphorylation and transphosphorylation of other proteins (UniProt Q9Y2I7). Mutations in the PIKFYVE gene are associated with corneal fleck dystrophy, a condition characterized by the accumulation of vacuoles in keratocytes (GeneCards). In therapeutic development, PIKfyve inhibitors are being explored for their ability to sensitize tumors to immune checkpoint blockade and to treat lysosomal storage disorders by modulating mTOR signaling (mdpi.com, researchgate.net).

Other names

PIKFYVEPIP5K3FAB1ZFYVE29CFDKIAA0981Phosphoinositide kinase FYVE-type zinc finger containing1-phosphatidylinositol 3-phosphate 5-kinase type IIIPIPkin-IIIp235Serine-protein kinase PIKFYVE

PIKfyve inhibitors bind to the ATP-binding site of the kinase domain, blocking the phosphorylation of PI3P to PI(3,5)P2 and PI to PI5P (nih.gov). This depletion of PI(3,5)P2 disrupts endosomal fission and lysosomal homeostasis, leading to the formation of large cytoplasmic vacuoles and the inhibition of autophagic flux (PubMed: 31427458). In the context of viral infection, this disruption prevents the release of viral RNA from endosomes into the cytosol (PubMed: 32697944). In cancer, it induces methuosis, a form of non-apoptotic cell death characterized by extreme vacuolation (acs.org).