@article {130539, title = {PI3P-dependent regulation of cell size and autophagy by phosphatidylinositol 5-phosphate 4-kinase.}, journal = {Life Sci Alliance}, volume = {6}, year = {2023}, month = {2023 Sep}, abstract = {

Phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 5-phosphate (PI5P) are low-abundance 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 role for PIP4K in regulating PI3P levels in Loss-of-function mutants of the only PIP4K gene show reduced cell size in salivary glands. PI3P levels are elevated in and reverting PI3P levels back towards WT, without changes in PI5P levels, can rescue the reduced cell size. mutants also show up-regulation in autophagy and the reduced cell size can be reverted by depleting Atg8a that is required for autophagy. Lastly, increasing PI3P levels in WT can phenocopy the reduction in cell size and associated autophagy up-regulation seen in Thus, our study reports a role for a PIP4K-regulated PI3P pool in the control of autophagy and cell size.

}, keywords = {Animals, Autophagy, Cell Size, Drosophila, Endosomes}, issn = {2575-1077}, doi = {10.26508/lsa.202301920}, author = {Ghosh, Avishek and Venugopal, Aishwarya and Shinde, Dhananjay and Sharma, Sanjeev and Krishnan, Meera and Mathre, Swarna and Krishnan, Harini and Saha, Sankhanil and Raghu, Padinjat} } @article {51226, title = {Functional analysis of the biochemical activity of mammalian phosphatidylinositol 5 phosphate 4-kinase enzymes.}, journal = {Biosci Rep}, year = {2019}, month = {2019 Feb 04}, abstract = {

Phosphatidylinositol 5 phosphate 4-kinase (PIP4K) are enzymes that catalyse the phosphorylation of PI5P to generate PI(4,5)P Mammalian genomes contain three genes, PIP4K2A, 2B and 2C and murine knockouts for these suggest important physiological roles The proteins encoded by PIP4K2A, 2B and 2C show widely varying specific activity ; PIP4K2A is highly active and PIP4K2C 2000 times less active and the relationship between this biochemical activity and function is unknown. By contrast the genome encodes a single PIP4K (dPIP4K) that shows high specific activity and loss of this enzyme results in reduced salivary gland cell size We find that the kinase activity of dPIP4K is essential for normal salivary gland cell size Despite their highly divergent specific activity, we find that all three mammalian PIP4K isoforms are able to enhance salivary gland cell size in implying a lack of correlation between activity measurement and function. Further, the kinase activity of PIP4K2C, reported to be almost inactive is required for function. Our findings suggest the existence of unidentified factors that regulate PIP4K enzyme activity .

}, issn = {1573-4935}, doi = {10.1042/BSR20182210}, author = {Mathre, Swarna and Reddy, Balasankara and Ramya, Visvanathan and Krishnan, Harini and Ghosh, Avishek and Raghu, Padinjat} } @article {57783, title = {Phosphatidylinositol 5 Phosphate 4-Kinase Regulates Plasma-Membrane PIP Turnover and Insulin Signaling.}, journal = {Cell Rep}, volume = {27}, year = {2019}, month = {2019 May 14}, pages = {1979-1990.e7}, abstract = {

Phosphatidylinositol 3,4,5-trisphosphate (PIP) generation at the plasma membrane is a key event during activation of receptor tyrosine kinases such as the insulin receptor required for normal growth and metabolism. We report that in Drosophila, phosphatidylinositol 5 phosphate 4-kinase (PIP4K) is required to limit PIP levels during insulin receptor activation. Depletion of PIP4K increases the levels of PIP produced in response to insulin stimulation. We find that PIP4K function at the plasma membrane enhances class I phosphoinositide 3-kinase (PI3K) activity, although the catalytic ability of PIP4K to produce phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] at the plasma membrane is dispensable for this regulation. Animals lacking PIP4K show enhanced insulin signaling-dependent phenotypes and are resistant to the metabolic consequences of a high-sugar diet, highlighting the importance of PIP4K in normal metabolism and development. Thus, PIP4Ks are key regulators of receptor tyrosine kinase signaling with implications for growth factor-dependent processes including tumor growth, T\ cell activation, and metabolism.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2019.04.084}, author = {Sharma, Sanjeev and Mathre, Swarna and Ramya, Visvanathan and Shinde, Dhananjay and Raghu, Padinjat} } @article {996, title = {RDGBα, a PtdIns-PtdOH transfer protein, regulates G-protein-coupled PtdIns(4,5)P2 signalling during Drosophila phototransduction.}, journal = {J Cell Sci}, volume = {128}, year = {2015}, month = {2015 Sep 1}, pages = {3330-44}, abstract = {

Many membrane receptors activate phospholipase C (PLC) during signalling, triggering changes in the levels of several plasma membrane lipids including phosphatidylinositol (PtdIns), phosphatidic acid (PtdOH) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. It is widely believed that exchange of lipids between the plasma membrane and endoplasmic reticulum (ER) is required to restore lipid homeostasis during PLC signalling, yet the mechanism remains unresolved. RDGBα (hereafter RDGB) is a multi-domain protein with a PtdIns transfer protein (PITP) domain (RDGB-PITPd). We find that, in vitro, the RDGB-PITPd binds and transfers both PtdOH and PtdIns. In Drosophila photoreceptors, which experience high rates of PLC activity, RDGB function is essential for phototransduction. We show that binding of PtdIns to RDGB-PITPd is essential for normal phototransduction; however, this property is insufficient to explain the in vivo function because another Drosophila PITP (encoded by vib) that also binds PtdIns cannot rescue the phenotypes of RDGB deletion. In RDGB mutants, PtdIns(4,5)P2 resynthesis at the plasma membrane following PLC activation is delayed and PtdOH levels elevate. Thus RDGB couples the turnover of both PtdIns and PtdOH, key lipid intermediates during G-protein-coupled PtdIns(4,5)P2 turnover.

}, issn = {1477-9137}, doi = {10.1242/jcs.173476}, author = {Yadav, Shweta and Garner, Kathryn and Georgiev, Plamen and Li, Michelle and Gomez-Espinosa, Evelyn and Panda, Aniruddha and Mathre, Swarna and Okkenhaug, Hanneke and Cockcroft, Shamshad and Raghu, Padinjat} }