Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time

Jin, Natsuko; Lang, Michael J.; Weisman, Lois S.

doi:10.1042/bst20150174

Cited by 76 publications

(76 citation statements)

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“…PI(3,5)P 2 plays an important role in late endosomal biogenesis. The reduction of PI(3,5)P 2 levels leads to the enlargement of late endosomes/lysosomes and contributes to a variety of diseases . To address the link between BORC and PI(3,5)P 2 levels on endosomal size regulation, we used two established inhibitors, which block PI(3,5)P 2 production; either by directly inhibiting PIKfyve with YM201636, or by blocking the upstream production of PI(3)P with VPS34‐IN1 (Supplementary Figure S3A) and measured their effects on the frequency of enlarged late endosomes/lysosomes in HT1080 cells (Figure A,B).…”

Section: Resultsmentioning

confidence: 99%

Biogenesis of lysosome‐related organelles complex‐1 (BORC) regulates late endosomal/lysosomal size through PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate

Yordanov

Hipolito

Liebscher

et al. 2019

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Mechanisms that control lysosomal function are essential for cellular homeostasis. Lysosomes adapt in size and number to cellular needs but little is known about the underlying molecular mechanism. We demonstrate that the late endosomal/lysosomal multimeric BLOC‐1‐related complex (BORC) regulates the size of these organelles via PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate [PI(3,5)P2] production. Deletion of the core BORC component Diaskedin led to increased levels of PI(3,5)P2, suggesting activation of PIKfyve, and resulted in enhanced lysosomal reformation and subsequent reduction in lysosomal size. This process required AMP‐activated protein kinase (AMPK), a known PIKfyve activator, and was additionally dependent on the late endosomal/lysosomal adaptor, mitogen‐activated protein kinases and mechanistic target of rapamycin activator (LAMTOR/Ragulator) complex. Consistently, in response to glucose limitation, AMPK activated PIKfyve, which induced lysosomal reformation with increased baseline autophagy and was coupled to a decrease in lysosomal size. These adaptations of the late endosomal/lysosomal system reversed under glucose replete growth conditions. In summary, our results demonstrate that BORC regulates lysosomal reformation and size in response to glucose availability.

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Section: Resultsmentioning

confidence: 99%

Biogenesis of lysosome‐related organelles complex‐1 (BORC) regulates late endosomal/lysosomal size through PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate

Yordanov

Hipolito

Liebscher

et al. 2019

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“…In yeast this complex includes Fig4, Vac14, Vac7, and Atg18; Fig4 and Vac14 are conserved in metazoans (Shisheva, 2008; McCartney et al , 2014a; Jin et al , 2016). Vac14, also called ArPIKfyve in mammals, consists almost entirely of HEAT repeats, and functions as a scaffold protein to form a complex with Fab1, Fig4, Vac7, and Atg18.…”

Section: Phosphatidylinositol 35-bisphosphate (Pi(35)p2)mentioning

confidence: 99%

PI5P and PI(3,5)P<sub>2</sub>: Minor, but Essential Phosphoinositides

Hasegawa

Strunk

Weisman

2017

Cell Struct. Funct.

128

119

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In most eukaryotes, phosphoinositides (PIs) have crucial roles in multiple cellular functions. Although the cellular levels of phosphatidylinositol 5-phosphate (PI5P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) are extremely low relative to some other PIs, emerging evidence demonstrates that both lipids are crucial for the endocytic pathway, intracellular signaling, and adaptation to stress. Mutations that causes defects in the biosynthesis of PI5P and PI(3,5)P2 are linked to human diseases including neurodegenerative disorders. Here, we review recent findings on cellular roles of PI5P and PI(3,5)P2, as well as the pathophysiological importance of these lipids.

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“…This enzyme phosphorylates phosphatidylinositol 3‐phosphate (PtdIns(3)P) at D‐5 and yields PtdIns(3,5)P 2 . Interestingly, E. histolytica does not appear to encode putative homologs of PtdIns(3,5)P 2 effector proteins such as Vps24p and Atg18p . Atg18p is essentially required for vesicle fission and membrane cycling at the vacuole .…”

Section: Resultsmentioning

confidence: 99%

PtdIns(4,5)P₂ is generated by a novel phosphatidylinositol 4‐phosphate 5‐kinase in the protist parasite Entamoeba histolytica

Sharma

Bhattacharya

2019

The FEBS Journal

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Entamoeba histolytica is an intestinal protist parasite that causes amoebiasis, a major source of morbidity and mortality in developing countries. Phosphoinositides are involved in signalling systems that have a role in invasion and pathogenesis of this parasite. Phosphatidylinositol 4‐phosphate 5‐kinase (PIP5K) catalyses the generation of phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P2), a key species of phosphoinositide that regulates various cellular processes. However, phosphatidylinositol phosphate kinase (PIPK) family of enzymes have not been characterized in E. histolytica. Here, we report the identification and characterization of type I PIPK (EhPIPKI) of E. histolytica. Computational analysis revealed homologs of type I and III PIPK family in E. histolytica and the absence of type II PIPK. In spite of low overall sequence identity, the kinase domain was found to be highly conserved. Interestingly, a unique insertion of a tandem repeat motif was observed in EhPIPKI distinguishing it from existing PIPKs of other organisms. Substrate profiling showed that EhPIPKI could phosphorylate at third and fifth hydroxyl positions of phosphatidylinositols, though the predominant substrate was phosphatidylinositol 4‐phosphate (PtdIns(4)P). Furthermore, EhPIPKI underwent intracellular cleavage close to the amino‐terminal, generating two distinct fragments Nter‐EhPIPKI (27p) and Cter‐EhPIPKI (47p). Immunofluorescence and cellular fractionation revealed that the full‐length EhPIPKI and the Cter‐EhPIPKI containing carboxyl‐terminal activation loop were present in the plasma membrane while the Nter‐EhPIPKI was observed in the cytosolic region. In conclusion, E. histolytica has a single EhPIPKI gene that displays novel properties of post‐translational processing, the presence of a repeat domain and substrate specificity not observed in any PIPK enzyme so far.

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Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time

Cited by 76 publications

References 77 publications

Biogenesis of lysosome‐related organelles complex‐1 (BORC) regulates late endosomal/lysosomal size through PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate

Biogenesis of lysosome‐related organelles complex‐1 (BORC) regulates late endosomal/lysosomal size through PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate

PI5P and PI(3,5)P<sub>2</sub>: Minor, but Essential Phosphoinositides

PtdIns(4,5)P₂ is generated by a novel phosphatidylinositol 4‐phosphate 5‐kinase in the protist parasite Entamoeba histolytica

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Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time

Cited by 76 publications

References 77 publications

Biogenesis of lysosome‐related organelles complex‐1 (BORC) regulates late endosomal/lysosomal size through PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate

Biogenesis of lysosome‐related organelles complex‐1 (BORC) regulates late endosomal/lysosomal size through PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate

PI5P and PI(3,5)P<sub>2</sub>: Minor, but Essential Phosphoinositides

PtdIns(4,5)P2 is generated by a novel phosphatidylinositol 4‐phosphate 5‐kinase in the protist parasite Entamoeba histolytica

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PtdIns(4,5)P₂ is generated by a novel phosphatidylinositol 4‐phosphate 5‐kinase in the protist parasite Entamoeba histolytica