A Highly Dynamic ER-Derived Phosphatidylinositol-Synthesizing Organelle Supplies Phosphoinositides to Cellular Membranes

Kim, Yeun Ju; Guzmán-Hernández, María Luisa; Balla, Tamás

doi:10.1016/j.devcel.2011.09.005

Cited by 178 publications

(220 citation statements)

References 48 publications

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“…The idea that PI synthesis is spatially regulated to control ER structure is consistent with recent work showing that phospholipid synthesis enzymes, including phosphatidylinositol synthase, are enriched in a Rab10-dependent ER subdomain and that this compartmentalization is important to prevent the excessive formation of ER sheets (Kim et al 2011;English and Voeltz 2012). How PI levels control the extent of ER sheet formation and whether the relevant lipid is PI itself or another PIderived PIP are important future questions.…”

Section: Resultssupporting

confidence: 60%

Spatial control of phospholipid flux restricts endoplasmic reticulum sheet formation to allow nuclear envelope breakdown

et al. 2014

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The nuclear envelope is a subdomain of the endoplasmic reticulum (ER). Here we characterize CNEP-1 (CTD [Cterminal domain] nuclear envelope phosphatase-1), a nuclear envelope-enriched activator of the ER-associated phosphatidic acid phosphatase lipin that promotes synthesis of major membrane phospholipids over phosphatidylinositol (PI). CNEP-1 inhibition led to ectopic ER sheets in the vicinity of the nucleus that encased the nuclear envelope and interfered with nuclear envelope breakdown (NEBD) during cell division. Reducing PI synthesis suppressed these phenotypes, indicating that CNEP-1 spatially regulates phospholipid flux, biasing it away from PI production in the vicinity of the nuclear envelope to prevent excess ER sheet formation and NEBD defects.Supplemental material is available for this article.Received September 11, 2013; revised version accepted December 13, 2013. The endoplasmic reticulum (ER) is composed of sheets and tubules bounded by a membrane bilayer that faces the cytoplasm on one side and an internal lumen on the other. The ER is partitioned into subdomains specialized for different functions. The nuclear envelope subdomain is a spherical sheet perforated by nuclear pores that encases the chromatin. The outer membrane and lumen of the nuclear envelope are directly contiguous with other ER structural elements, whereas passage of proteins to the inner nuclear membrane (INM) is gated by the nuclear pores (Hetzer 2010;English and Voeltz 2013). The chromatin-facing INM is associated with the nuclear lamina, a dense filament meshwork that provides structural support (Hetzer 2010;Gerace and Huber 2012).The ER also serves as a platform for de novo phospholipid synthesis (Fagone and Jackowski 2009;Lagace and Ridgway 2013). A central player is the conserved phosphatase lipin, which converts phosphatidic acid (PA) to diacylglycerol (DAG) Siniossoglou 2013). In metazoans, lipin is at a branching point in the phospholipid synthesis pathway; the major building blocks of membrane bilayers (phosphatidylcholine [PC] and phosphatidylethanolamine [PE]) are synthesized from the lipin product DAG, whereas phosphatidylinositol (PI) is synthesized from the lipin substrate PA Lagace and Ridgway 2013;Siniossoglou 2013). PI is converted to phosphoinositides (PIPs) when transported to other organelles that house specific PIP kinases and phosphatases (Balla 2013). Within the ER, PC and PE make up >70% of total phospholipid, whereas PI makes up <10% (van Meer et al. 2008). In metazoans, decreased lipin activity is predicted to shift phospholipid flux away from production of DAG and the major membrane phospholipids PC and PE toward the production of PI. This is in contrast to budding yeast, where a pathway that is not present in metazoans (the CDP-DAG pathway) (Supplemental Fig. S1A) converts PA to major membrane phospholipids (Carman and Han 2011;Siniossoglou 2013). Thus, lipin inhibition in budding yeast leads to an increase in all phospholipids and an abnormal expansion of the nuclear envelope that does not occu...

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Section: Resultssupporting

confidence: 60%

Spatial control of phospholipid flux restricts endoplasmic reticulum sheet formation to allow nuclear envelope breakdown

et al. 2014

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“…This model was supported by both genetic and physiological studies on RdgB in Drosophila and its role in phototransduction cascade (Harris and Stark 1977;Vihtelic et al 1991Vihtelic et al , 1993Hardie et al 2001). Nevertheless, other studies suggest that PITPs are not involved in PI transport to the PM (Milligan et al 1997;Li et al 2000), and more recently, that PI could be delivered to the PM by specialized membrane compartments that carry PIS (Kim et al 2011). Studies on Sec14p, the major PITP in budding yeast, also suggest that it does not act as PI/PC-transfer protein in intact cells, but rather, as a scaffold that regulates the production of phosphoinositides and PC (Bankaitis et al 2010).…”

Section: Nonvesicular Transport Of Phospholipids In Intact Cellsmentioning

confidence: 67%

“…De novo biosynthesis of PC and PE via the Kennedy pathway occurs at the ER and requires DAG, which is derived from PA by PA phosphatase (PAP). DAG kinase (DGK) phosphorylates DAG back to PA. PI synthesis also requires PA, whereas PS synthesis is mediated by PSS1 andspecialized membrane compartment that is derived from the ER and makes ample contacts with other cellular membranes including the plasma membrane (PM), suggesting that PI could be synthesized at the PM (Kim et al 2011). This might be critical for many cellular responses especially because PI is a precursor of various phosphoinositide species (PI3P, PI4P, PI5P, PI [3,4] (Balla et al 2009).…”

Section: De Novo Lipid Biosynthesis In the Ermentioning

confidence: 99%

Nonvesicular Lipid Transfer from the Endoplasmic Reticulum

Lev

2012

Cold Spring Harbor Perspectives in Biology

103

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“…It represents a summary and working hypothesis about the relations of pools of PI, PI(4)P, and PI(4,5)P 2 in three organelles: PM, Golgi, and ER. In addition, it shows phosphoinositide transfer proteins (PITPs) that deliver PI to the PM (46) and a small, mobile organelle dubbed PIPerosome that has been postulated to synthesize and deliver PI to several cellular compartments (47). Our experiments in tsA-201 cells show that (i) plasma membrane PI(4,5)P 2 levels are supported by at least two precursor pools of PI(4)P, one in the PM and the other in the Golgi; (ii) selectively depleting PI(4)P at either location immediately initiates a slow reduction of KCNQ2/3 current or PH probe intensity, suggesting that the PI(4)P contributions from both pools are dynamic and ongoing; (iii) the contribution of the PM PI(4)P pool seems greater than that of the Golgi; (iv) translocating a 5-phosphatase to the Golgi has no effect on KCNQ2/3 currents, suggesting that the Golgi has no significant PI(4,5)P 2 pool; (v) inhibiting myosin II-mediated transport produces declines in PM PI(4,5)P 2 similar to those with depletion of Golgi PI(4)P, indicating continuous PI(4)P vesicular traffic from the Golgi to the PM; and (vi) endogenous Sac1 is capable of dephosphorylating Golgi PI(4)P and thus potentially acts as a regulator of PM PI(4,5)P 2 .…”

Section: Discussionmentioning

confidence: 99%

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P ₂ and maintenance of KCNQ2/3 ion channel current

Dickson

Jensen

Hille

2014

Proc. Natl. Acad. Sci. U.S.A.

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Plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] regulates the activity of many ion channels and other membrane-associated proteins. To determine precursor sources of the PM PI(4,5)P 2 pool in tsA-201 cells, we monitored KCNQ2/3 channel currents and translocation of PH PLCδ1 domains as real-time indicators of PM PI(4,5)P 2 , and translocation of PH OSH2×2 , and PH OSH1 domains as indicators of PM and Golgi phosphatidylinositol 4-phosphate [PI(4)P], respectively. We selectively depleted PI(4)P pools at the PM, Golgi, or both using the rapamycin-recruitable lipid 4-phosphatases. Depleting PI(4)P at the PM with a recruitable 4-phosphatase (Sac1) results in a decrease of PI(4,5)P 2 measured by electrical or optical indicators. Depleting PI(4)P at the Golgi with the 4-phosphatase or disrupting membrane-transporting motors induces a decline in PM PI(4,5)P 2 . Depleting PI(4)P simultaneously at both the Golgi and the PM induces a larger decrease of PI(4,5)P 2 . The decline of PI(4,5)P 2 following 4-phosphatase recruitment takes 1-2 min. Recruiting the endoplasmic reticulum (ER) toward the Golgi membranes mimics the effects of depleting PI(4)P at the Golgi, apparently due to the trans actions of endogenous ER Sac1. Thus, maintenance of the PM pool of PI(4,5)P 2 appears to depend on precursor pools of PI(4)P both in the PM and in the Golgi. The decrease in PM PI(4,5)P 2 when Sac1 is recruited to the Golgi suggests that the Golgi contribution is ongoing and that PI (4,5)P 2 production may be coupled to important cell biological processes such as membrane trafficking or lipid transfer activity.phosphoinositides | wortmannin | pleckstrin homology domain T his paper concerns the dynamics of cellular pools of phosphoinositides, a family of phospholipids located on the cytoplasmic leaflet of cellular membranes, that maintain cell structure, cell motility, membrane identity, and membrane trafficking; they also play key roles in signal transduction (1). Phosphatidylinositol (PI) can be phosphorylated at three positions to generate seven additional species. The subcellular localization of each phosphoinositide is tightly governed by the concurrent presence of lipid kinases and lipid phosphatases (2, 3), giving each membrane within the cell a unique and dynamic phosphoinositide signature (4). Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] is localized to the inner leaflet of the plasma membrane (PM) and is the major substrate of phospholipase C (PLC). As a consequence, PI(4,5)P 2 levels are dynamically regulated by G q -coupled receptors activating PLC. The activity of lipid kinases and phosphatases also can be modulated by signaling; for example, a PI 4-kinase, when associated with neuronal calcium sensor-1, is accelerated in response to elevated calcium that occurs with PI(4,5)P 2 cleavage (5). In addition, transient apposition between organelles can alter phosphoinositide levels by presenting membrane-bound phosphatases in trans. For example, the endoplasmic reticulum (ER) can make contacts with the...

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A Highly Dynamic ER-Derived Phosphatidylinositol-Synthesizing Organelle Supplies Phosphoinositides to Cellular Membranes

Cited by 178 publications

References 48 publications

Spatial control of phospholipid flux restricts endoplasmic reticulum sheet formation to allow nuclear envelope breakdown

Spatial control of phospholipid flux restricts endoplasmic reticulum sheet formation to allow nuclear envelope breakdown

Nonvesicular Lipid Transfer from the Endoplasmic Reticulum

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P ₂ and maintenance of KCNQ2/3 ion channel current

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A Highly Dynamic ER-Derived Phosphatidylinositol-Synthesizing Organelle Supplies Phosphoinositides to Cellular Membranes

Cited by 178 publications

References 48 publications

Spatial control of phospholipid flux restricts endoplasmic reticulum sheet formation to allow nuclear envelope breakdown

Spatial control of phospholipid flux restricts endoplasmic reticulum sheet formation to allow nuclear envelope breakdown

Nonvesicular Lipid Transfer from the Endoplasmic Reticulum

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P 2 and maintenance of KCNQ2/3 ion channel current

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Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P ₂ and maintenance of KCNQ2/3 ion channel current