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Vps34 derived phosphatidylinositol 3-monophosphate modulates megakaryocyte maturation and proplatelet production through late endosomes/lysosomes

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Vps34 derived phosphatidylinositol 3-monophosphate modulates megakaryocyte maturation and proplatelet production through late endosomes/lysosomes. / Bertović, Ivana; Kurelić, Roberta; Milošević, Ira; Bender, Markus; Krauss, Michael; Haucke, Volker; Jurak Begonja, Antonija.

In: J THROMB HAEMOST, Vol. 18, No. 7, 07.2020, p. 1756-1772.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Bertović, I, Kurelić, R, Milošević, I, Bender, M, Krauss, M, Haucke, V & Jurak Begonja, A 2020, 'Vps34 derived phosphatidylinositol 3-monophosphate modulates megakaryocyte maturation and proplatelet production through late endosomes/lysosomes', J THROMB HAEMOST, vol. 18, no. 7, pp. 1756-1772. https://doi.org/10.1111/jth.14764

APA

Bertović, I., Kurelić, R., Milošević, I., Bender, M., Krauss, M., Haucke, V., & Jurak Begonja, A. (2020). Vps34 derived phosphatidylinositol 3-monophosphate modulates megakaryocyte maturation and proplatelet production through late endosomes/lysosomes. J THROMB HAEMOST, 18(7), 1756-1772. https://doi.org/10.1111/jth.14764

Vancouver

Bertović I, Kurelić R, Milošević I, Bender M, Krauss M, Haucke V et al. Vps34 derived phosphatidylinositol 3-monophosphate modulates megakaryocyte maturation and proplatelet production through late endosomes/lysosomes. J THROMB HAEMOST. 2020 Jul;18(7):1756-1772. https://doi.org/10.1111/jth.14764

Bibtex

@article{0a8769ba7bd6488cbff97a1eaa0adab2,
title = "Vps34 derived phosphatidylinositol 3-monophosphate modulates megakaryocyte maturation and proplatelet production through late endosomes/lysosomes",
abstract = "BACKGROUND: Development of platelet precursor cells, megakaryocytes (MKs), implies an increase in their size; formation of the elaborate demarcation membrane system (DMS); and extension of branched cytoplasmic structures, proplatelets, that will release platelets. The membrane source(s) for MK expansion and proplatelet formation have remained elusive.OBJECTIVE: We hypothesized that traffic of membranes regulated by phosphatidylinositol 3-monophosphate (PI3P) contributes to MK maturation and proplatelet formation.RESULTS: In immature MKs, PI3P produced by the lipid kinase Vps34 is confined to perinuclear early endosomes (EE), while in mature MKs PI3P shifts to late endosomes and lysosomes (LE/Lys). PI3P partially colocalized with the plasma membrane marker phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 ) and with LE/Lys in mature MKs, suggests that PI3P-containing LE/Lys membranes contribute to MK expansion and proplatelet formation. Consistently, we found that sequestration of PI3P, specific pharmacological inhibition of Vps34-mediated PI3P production, or depletion of PI3P by PI3-phosphatase (MTM1)-mediated hydrolysis potently blocked proplatelet formation. Moreover, Vps34 inhibition led to the intracellular accumulation of enlarged LE/Lys, and decreased expression of surface LE/Lys markers. Inhibiting Vps34 at earlier MK stages caused aberrant DMS development. Finally, inhibition of LE/Lys membrane fusion by a dominant negative mutant of the small GTPase Rab7 or pharmacological inhibition of PI3P conversion into PI(3,5)P2 led to enlarged LE/Lys, reduced surface levels of LE/Lys markers, and decreased proplatelet formation.CONCLUSION: Our results suggest that PI3P-positive LE/Lys contribute to the membrane growth and proplatelet formation in MKs by their translocation to the cell periphery and fusion with the plasma membrane.",
keywords = "Blood Platelets, Endosomes, Lysosomes, Megakaryocytes, Phosphatidylinositol Phosphates",
author = "Ivana Bertovi{\'c} and Roberta Kureli{\'c} and Ira Milo{\v s}evi{\'c} and Markus Bender and Michael Krauss and Volker Haucke and {Jurak Begonja}, Antonija",
note = "{\textcopyright} 2020 International Society on Thrombosis and Haemostasis.",
year = "2020",
month = jul,
doi = "10.1111/jth.14764",
language = "English",
volume = "18",
pages = "1756--1772",
journal = "J THROMB HAEMOST",
issn = "1538-7933",
publisher = "Wiley-Blackwell",
number = "7",

}

RIS

TY - JOUR

T1 - Vps34 derived phosphatidylinositol 3-monophosphate modulates megakaryocyte maturation and proplatelet production through late endosomes/lysosomes

AU - Bertović, Ivana

AU - Kurelić, Roberta

AU - Milošević, Ira

AU - Bender, Markus

AU - Krauss, Michael

AU - Haucke, Volker

AU - Jurak Begonja, Antonija

N1 - © 2020 International Society on Thrombosis and Haemostasis.

PY - 2020/7

Y1 - 2020/7

N2 - BACKGROUND: Development of platelet precursor cells, megakaryocytes (MKs), implies an increase in their size; formation of the elaborate demarcation membrane system (DMS); and extension of branched cytoplasmic structures, proplatelets, that will release platelets. The membrane source(s) for MK expansion and proplatelet formation have remained elusive.OBJECTIVE: We hypothesized that traffic of membranes regulated by phosphatidylinositol 3-monophosphate (PI3P) contributes to MK maturation and proplatelet formation.RESULTS: In immature MKs, PI3P produced by the lipid kinase Vps34 is confined to perinuclear early endosomes (EE), while in mature MKs PI3P shifts to late endosomes and lysosomes (LE/Lys). PI3P partially colocalized with the plasma membrane marker phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 ) and with LE/Lys in mature MKs, suggests that PI3P-containing LE/Lys membranes contribute to MK expansion and proplatelet formation. Consistently, we found that sequestration of PI3P, specific pharmacological inhibition of Vps34-mediated PI3P production, or depletion of PI3P by PI3-phosphatase (MTM1)-mediated hydrolysis potently blocked proplatelet formation. Moreover, Vps34 inhibition led to the intracellular accumulation of enlarged LE/Lys, and decreased expression of surface LE/Lys markers. Inhibiting Vps34 at earlier MK stages caused aberrant DMS development. Finally, inhibition of LE/Lys membrane fusion by a dominant negative mutant of the small GTPase Rab7 or pharmacological inhibition of PI3P conversion into PI(3,5)P2 led to enlarged LE/Lys, reduced surface levels of LE/Lys markers, and decreased proplatelet formation.CONCLUSION: Our results suggest that PI3P-positive LE/Lys contribute to the membrane growth and proplatelet formation in MKs by their translocation to the cell periphery and fusion with the plasma membrane.

AB - BACKGROUND: Development of platelet precursor cells, megakaryocytes (MKs), implies an increase in their size; formation of the elaborate demarcation membrane system (DMS); and extension of branched cytoplasmic structures, proplatelets, that will release platelets. The membrane source(s) for MK expansion and proplatelet formation have remained elusive.OBJECTIVE: We hypothesized that traffic of membranes regulated by phosphatidylinositol 3-monophosphate (PI3P) contributes to MK maturation and proplatelet formation.RESULTS: In immature MKs, PI3P produced by the lipid kinase Vps34 is confined to perinuclear early endosomes (EE), while in mature MKs PI3P shifts to late endosomes and lysosomes (LE/Lys). PI3P partially colocalized with the plasma membrane marker phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 ) and with LE/Lys in mature MKs, suggests that PI3P-containing LE/Lys membranes contribute to MK expansion and proplatelet formation. Consistently, we found that sequestration of PI3P, specific pharmacological inhibition of Vps34-mediated PI3P production, or depletion of PI3P by PI3-phosphatase (MTM1)-mediated hydrolysis potently blocked proplatelet formation. Moreover, Vps34 inhibition led to the intracellular accumulation of enlarged LE/Lys, and decreased expression of surface LE/Lys markers. Inhibiting Vps34 at earlier MK stages caused aberrant DMS development. Finally, inhibition of LE/Lys membrane fusion by a dominant negative mutant of the small GTPase Rab7 or pharmacological inhibition of PI3P conversion into PI(3,5)P2 led to enlarged LE/Lys, reduced surface levels of LE/Lys markers, and decreased proplatelet formation.CONCLUSION: Our results suggest that PI3P-positive LE/Lys contribute to the membrane growth and proplatelet formation in MKs by their translocation to the cell periphery and fusion with the plasma membrane.

KW - Blood Platelets

KW - Endosomes

KW - Lysosomes

KW - Megakaryocytes

KW - Phosphatidylinositol Phosphates

U2 - 10.1111/jth.14764

DO - 10.1111/jth.14764

M3 - SCORING: Journal article

C2 - 32056354

VL - 18

SP - 1756

EP - 1772

JO - J THROMB HAEMOST

JF - J THROMB HAEMOST

SN - 1538-7933

IS - 7

ER -