PI3P dependent regulation of cell size and autophagy by phosphatidylinositol 5-phosphate 4-kinase

Abstract

Phosphatidylinositol 3-phosphate (PI3P) and Phosphatidylinositol 5-phosphate (PI5P) are low abundant phosphoinositides crucial for key cellular events such as endosomal trafficking and autophagy. Phosphatidylinositol 5-phosphate 4-kinase (PIP4K) is an enzyme that regulates PI5P in vivo but can act on both PI5P and PI3P, in vitro. In this study, we report a novel role for PIP4K in regulating PI3P levels in Drosophila tissues. Loss-of-function mutants of the only PIP4K gene in Drosophila (dPIP4K29) show reduced cell size in larval salivary glands. We find that PI3P levels are elevated in dPIP4K29 tissues and that reverting PI3P levels back towards wild type, without changes in PI5P levels, can also rescue the reduced cell size phenotype. dPIP4K29 mutants also show an upregulation in autophagy and the reduced cell size can be reverted by decreasing Atg8a, that is required for autophagosome maturation. Lastly, increasing PI3P levels in wild type salivary glands can phenocopy the reduction in cell size and associated upregulation of autophagy seen in dPIP4K29. Thus, our study reports for the first time, a role for a PIP4K-regulated PI3P pool in the control of autophagy and cell size regulation that may explain the reported role of PIP4K in regulating neurodegeneration and tumour growth.

A genetic and physiological model of renal dysfunction in Lowe syndrome

“…We analyzed if the enhanced lysotracker staining was due to increased lysosomes. To visualize lysosomes we developed a construct in which the lysosome targeting sequence (LTS) is fused to mCherry (LTS::mCherry) (Ghosh et al, 2023). When expressed in control nephrocytes, LTS::mCherry marks punctate vesicular structures that can be quantified using confocal microscopy.…”

“…gRNAP2dual-CG3573V, UAS-Cas9-T2A-eGFP used to generate nephrocyte specific knockout has been previously described (Trivedi et al, 2020). UAS-LTS::mCherry was generated as mentioned in (Ghosh et al, 2023).…”

Modelling PIP4K2A inhibitory activity of 1,7-naphthyridine analogues using machine learning and molecular docking studies

“…7 Over the years, researchers have targeted the mechanism by which cancer cells adapt to their micro-environment. [8][9][10] Phosphoinositide-3-kinase (PI3K) signal transduction pathway is the most important pathway that controls the metabolic adaptation of cancer cells. 8 Hence, developing drugs that can effectively disrupt the PI3K signal transduction pathway is of primary interests to researchers.…”

“…9 The conversion of phosphatidylinositol-5-phosphate (PI5P) into phosphatidylinositol 4,5-bisphosphate (PI4,5P2), an important step in PI3K signal transduction is catalysed by PIP4K2s, a type II kinase inhibitor. [10][11][12][13][14] Because of the number of important cellular processes such as vesicle transport, adhesion, cell proliferation, and apoptosis that depends on this conversion, PIP4K2A have been inhibitors are intricately involved in many biological processes that are responsible for malignant phenotype. furthermore, PIP4K2A has been reported to exhibit a synthetic lethal interaction with the tumor suppressor gene p53.…”