Phospholipase D1 Explained

Phospholipase D₁ (PLD1) is an enzyme that in humans is encoded by the PLD1 gene,^{[1] [2]} though analogues are found in plants, fungi, prokaryotes, and even viruses.^[3]

History

The possibility of PLD1 was first mentioned in 1947 by authors Hanahan and Chaikoff at Berkeley when describing a carrot enzyme that could "[split] choline from phospholipids."^[4] PLD was first derived in mammals in 1975 by Saito and Kanfer, who noted its activity in rats.^[5] PLD was first cloned from HeLa cell cDNA in 1995, while mammalian PLD1 was first cloned from a rat in 1997.

Function

Phosphatidylcholine (PC)-specific phospholipases D (PLDs) catalyze the hydrolysis of PC to produce phosphatidic acid (PA) and choline. A range of agonists acting through G protein-coupled receptors and receptor tyrosine kinases stimulate this hydrolysis. PC-specific PLD activity has been implicated in numerous cellular pathways, including membrane trafficking, signal transduction, platelet coagulation, mitosis, apoptosis, and the creation of cytoplasmic lipid droplets.^{[6] [7]}

Membrane trafficking

PLD1 has been shown to associate at the plasma membrane, late endosome,^[8] early endosome, and the Golgi apparatus. There is evidence that PA is able to assist in negative membrane curvature due to its head group being smaller than in many other lipids. One experiment with PLD1 knockout showed a significant reduction in the number of exocytotic fusion events, implying a strong role in exocytosis.^[9]

Signal transduction

PLD1 may play a role in some cells in the endocytosis of signaling receptors or exocytosis of signaling molecules. For example, one experiment in B cells showed that limiting PLD1 led to significantly reduced endocytosis of the B cell receptor. Another experiment showed that knocking out PLD1 may hinder the ability of mice to secrete catecholamines, molecules that are essential for vesicular communication across the body.

Structure

Mammalian PLD1 has several domains for activators, inhibitors, and catalysis, which it shares with PLD2. Domains for both activation and inhibition are referred to as the phox homology (PX) and pleckstrin homology (PH) domains. The catalytic domain consists of two HKD regions, so named for three of the amino acids that are key in catalysis. These domains are conserved across many organisms. There are two splice variants of the protein, PLD1a and PLD1b, but they do not seem to localize any differently.

Applications

Alzheimer's disease

PA, which is produced in part by PLD1, seems to be involved in the movement of β-amyloid, which could precede amyloidogenesis.^[10]

Cancer

certain rat tumors with dominant negative PLD do not appear to form new colonies or tumors.

Thrombosis

PLD knockout mice appear to have reduced occlusion, thus offsetting thrombosis.

Type II Diabetes

the protein PED/PEA15 is often elevated in type II diabetic patients, thus enhancing PLD1 activity, and in turn impairing insulin.

Interactions

Phospholipase D1 has been shown to interact with:

• Alpha-synuclein,^[11]
• Amphiphysin,
• BIN1,^[12]
• CDC42,^[13]
• PEA15,^[14]
• Protein kinase N1^[15]
• RALA,^{[16] [17]} and
• RHOA.^{[18] [19]}

Inhibitors

• Calphostin-c, an inhibitor
• VU-0359595: 1,700-fold selective versus phospholipase D2, IC₅₀ = 3.7nM.^[20]

Further reading

• Hammond SM, Jenco JM, Nakashima S, Cadwallader K, Gu Q, Cook S, Nozawa Y, Prestwich GD, Frohman MA, Morris AJ . 6 . Characterization of two alternately spliced forms of phospholipase D1. Activation of the purified enzymes by phosphatidylinositol 4,5-bisphosphate, ADP-ribosylation factor, and Rho family monomeric GTP-binding proteins and protein kinase C-alpha . The Journal of Biological Chemistry . 272 . 6 . 3860–8 . February 1997 . 9013646 . 10.1074/jbc.272.6.3860 . free .
• Luo JQ, Liu X, Hammond SM, Colley WC, Feig LA, Frohman MA, Morris AJ, Foster DA . 6 . RalA interacts directly with the Arf-responsive, PIP2-dependent phospholipase D1 . Biochemical and Biophysical Research Communications . 235 . 3 . 854–9 . June 1997 . 9207251 . 10.1006/bbrc.1997.6793 . free .
• Colley WC, Sung TC, Roll R, Jenco J, Hammond SM, Altshuller Y, Bar-Sagi D, Morris AJ, Frohman MA . 6 . Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization . Current Biology . 7 . 3 . 191–201 . March 1997 . 9395408 . 10.1016/S0960-9822(97)70090-3 . 14008613 . free . 1997CBio....7..191C .
• Bae CD, Min DS, Fleming IN, Exton JH . Determination of interaction sites on the small G protein RhoA for phospholipase D . The Journal of Biological Chemistry . 273 . 19 . 11596–604 . May 1998 . 9565577 . 10.1074/jbc.273.19.11596 . free .
• Lopez I, Arnold RS, Lambeth JD . Cloning and initial characterization of a human phospholipase D2 (hPLD2). ADP-ribosylation factor regulates hPLD2 . The Journal of Biological Chemistry . 273 . 21 . 12846–52 . May 1998 . 9582313 . 10.1074/jbc.273.21.12846 . free .
• Kim JH, Lee SD, Han JM, Lee TG, Kim Y, Park JB, Lambeth JD, Suh PG, Ryu SH . 6 . Activation of phospholipase D1 by direct interaction with ADP-ribosylation factor 1 and RalA . FEBS Letters . 430 . 3 . 231–5 . July 1998 . 9688545 . 10.1016/S0014-5793(98)00661-9 . 36075513 .
• Steed PM, Clark KL, Boyar WC, Lasala DJ . Characterization of human PLD2 and the analysis of PLD isoform splice variants . FASEB Journal . 12 . 13 . 1309–17 . October 1998 . 9761774 . 10.1096/fasebj.12.13.1309 . free . 27394831 .
• Kim JH, Han JM, Lee S, Kim Y, Lee TG, Park JB, Lee SD, Suh PG, Ryu SH . 6 . Phospholipase D1 in caveolae: regulation by protein kinase Calpha and caveolin-1 . Biochemistry . 38 . 12 . 3763–9 . March 1999 . 10090765 . 10.1021/bi982478+ .
• Kim Y, Han JM, Park JB, Lee SD, Oh YS, Chung C, Lee TG, Kim JH, Park SK, Yoo JS, Suh PG, Ryu SH . 6 . Phosphorylation and activation of phospholipase D1 by protein kinase C in vivo: determination of multiple phosphorylation sites . Biochemistry . 38 . 32 . 10344–51 . August 1999 . 10441128 . 10.1021/bi990579h .
• Walker SJ, Wu WJ, Cerione RA, Brown HA . Activation of phospholipase D1 by Cdc42 requires the Rho insert region . The Journal of Biological Chemistry . 275 . 21 . 15665–8 . May 2000 . 10747870 . 10.1074/jbc.M000076200 . free .
• Suzuki J, Yamazaki Y, Li G, Kaziro Y, Koide H, Guang L . Involvement of Ras and Ral in chemotactic migration of skeletal myoblasts . Molecular and Cellular Biology . 20 . 13 . 4658–65 . July 2000 . 10848592 . 85875 . 10.1128/MCB.20.13.4658-4665.2000 .
• Zhang Y, Redina O, Altshuller YM, Yamazaki M, Ramos J, Chneiweiss H, Kanaho Y, Frohman MA . 6 . Regulation of expression of phospholipase D1 and D2 by PEA-15, a novel protein that interacts with them . The Journal of Biological Chemistry . 275 . 45 . 35224–32 . November 2000 . 10926929 . 10.1074/jbc.M003329200 . free.
• Divecha N, Roefs M, Halstead JR, D'Andrea S, Fernandez-Borga M, Oomen L, Saqib KM, Wakelam MJ, D'Santos C . 6 . Interaction of the type Ialpha PIPkinase with phospholipase D: a role for the local generation of phosphatidylinositol 4, 5-bisphosphate in the regulation of PLD2 activity . The EMBO Journal . 19 . 20 . 5440–9 . October 2000 . 11032811 . 314009 . 10.1093/emboj/19.20.5440 .
• Oishi K, Takahashi M, Mukai H, Banno Y, Nakashima S, Kanaho Y, Nozawa Y, Ono Y . 6 . PKN regulates phospholipase D1 through direct interaction . The Journal of Biological Chemistry . 276 . 21 . 18096–101 . May 2001 . 11259428 . 10.1074/jbc.M010646200 . free .
• Cai S, Exton JH . Determination of interaction sites of phospholipase D1 for RhoA . The Biochemical Journal . 355 . Pt 3 . 779–85 . May 2001 . 11311142 . 1221795 . 10.1042/bj3550779 .
• Lee S, Park JB, Kim JH, Kim Y, Kim JH, Shin KJ, Lee JS, Ha SH, Suh PG, Ryu SH . 6 . Actin directly interacts with phospholipase D, inhibiting its activity . The Journal of Biological Chemistry . 276 . 30 . 28252–60 . July 2001 . 11373276 . 10.1074/jbc.M008521200 . free .
• Hughes WE, Parker PJ . Endosomal localization of phospholipase D 1a and 1b is defined by the C-termini of the proteins, and is independent of activity . The Biochemical Journal . 356 . Pt 3 . 727–36 . June 2001 . 11389680 . 1221899 . 10.1042/0264-6021:3560727 .
• Min DS, Ahn BH, Jo YH . Differential tyrosine phosphorylation of phospholipase D isozymes by hydrogen peroxide and the epidermal growth factor in A431 epidermoid carcinoma cells . Molecules and Cells . 11 . 3 . 369–78 . June 2001 . 10.1016/S1016-8478(23)17049-X . 11459228 . free .

Notes and References

1. Park SH, Chun YH, Ryu SH, Suh PG, Kim H . Assignment of human PLD1 to human chromosome band 3q26 by fluorescence in situ hybridization . Cytogenetics and Cell Genetics . 82 . 3–4 . 224 . February 1999 . 9858822 . 10.1159/000015105 . 46791637 .
2. Hammond SM, Altshuller YM, Sung TC, Rudge SA, Rose K, Engebrecht J, Morris AJ, Frohman MA . 6 . Human ADP-ribosylation factor-activated phosphatidylcholine-specific phospholipase D defines a new and highly conserved gene family . The Journal of Biological Chemistry . 270 . 50 . 29640–3 . December 1995 . 8530346 . 10.1074/jbc.270.50.29640 . free .
3. Selvy PE, Lavieri RR, Lindsley CW, Brown HA . Phospholipase D: enzymology, functionality, and chemical modulation . Chemical Reviews . 111 . 10 . 6064–119 . October 2011 . 21936578 . 3233269 . 10.1021/cr200296t .
4. Hanahan DJ, Chaikoff IL . The phosphorus-containing lipides of the carrot . The Journal of Biological Chemistry . 168 . 1 . 233–40 . April 1947 . 10.1016/S0021-9258(17)35110-4 . 20291081 . free .
5. Jenkins GM, Frohman MA . Phospholipase D: a lipid centric review . Cellular and Molecular Life Sciences . 62 . 19–20 . 2305–16 . October 2005 . 16143829 . 10.1007/s00018-005-5195-z . 26447185 . 11139095 .
6. Web site: Entrez Gene: PLD1 phospholipase D1, phosphatidylcholine-specific.
7. Andersson L, Boström P, Ericson J, Rutberg M, Magnusson B, Marchesan D, Ruiz M, Asp L, Huang P, Frohman MA, Borén J, Olofsson SO . 6 . PLD1 and ERK2 regulate cytosolic lipid droplet formation . Journal of Cell Science . 119 . Pt 11 . 2246–57 . June 2006 . 16723731 . 10.1242/jcs.02941 . 1628874 . free .
8. Donaldson JG . Phospholipase D in endocytosis and endosomal recycling pathways . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1791 . 9 . 845–9 . September 2009 . 19540357 . 10.1016/j.bbalip.2009.05.011 . 2731818 .
9. Tanguy E, Costé de Bagneaux P, Kassas N, Ammar MR, Wang Q, Haeberlé AM, Raherindratsara J, Fouillen L, Renard PY, Montero-Hadjadje M, Chasserot-Golaz S, Ory S, Gasman S, Bader MF, Vitale N . 6 . Mono- and Poly-unsaturated Phosphatidic Acid Regulate Distinct Steps of Regulated Exocytosis in Neuroendocrine Cells . Cell Reports . 32 . 7 . 108026 . August 2020 . 32814056 . 10.1016/j.celrep.2020.108026 . free .
10. Thakur R, Naik A, Panda A, Raghu P . Regulation of Membrane Turnover by Phosphatidic Acid: Cellular Functions and Disease Implications . Frontiers in Cell and Developmental Biology . 7 . 83 . 2019-06-04 . 31231646 . 10.3389/fcell.2019.00083 . 6559011 . free .
11. Ahn BH, Rhim H, Kim SY, Sung YM, Lee MY, Choi JY, Wolozin B, Chang JS, Lee YH, Kwon TK, Chung KC, Yoon SH, Hahn SJ, Kim MS, Jo YH, Min DS . 6 . alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells . The Journal of Biological Chemistry . 277 . 14 . 12334–42 . April 2002 . 11821392 . 10.1074/jbc.M110414200 . free .
12. Lee C, Kim SR, Chung JK, Frohman MA, Kilimann MW, Rhee SG . Inhibition of phospholipase D by amphiphysins . The Journal of Biological Chemistry . 275 . 25 . 18751–8 . June 2000 . 10764771 . 10.1074/jbc.M001695200 . free .
13. Walker SJ, Wu WJ, Cerione RA, Brown HA . Activation of phospholipase D1 by Cdc42 requires the Rho insert region . The Journal of Biological Chemistry . 275 . 21 . 15665–8 . May 2000 . 10747870 . 10.1074/jbc.M000076200 . free .
14. Zhang Y, Redina O, Altshuller YM, Yamazaki M, Ramos J, Chneiweiss H, Kanaho Y, Frohman MA . 6 . Regulation of expression of phospholipase D1 and D2 by PEA-15, a novel protein that interacts with them . The Journal of Biological Chemistry . 275 . 45 . 35224–32 . November 2000 . 10926929 . 10.1074/jbc.M003329200 . free.
15. Oishi K, Takahashi M, Mukai H, Banno Y, Nakashima S, Kanaho Y, Nozawa Y, Ono Y . 6 . PKN regulates phospholipase D1 through direct interaction . The Journal of Biological Chemistry . 276 . 21 . 18096–101 . May 2001 . 11259428 . 10.1074/jbc.M010646200 . free .
16. Luo JQ, Liu X, Hammond SM, Colley WC, Feig LA, Frohman MA, Morris AJ, Foster DA . 6 . RalA interacts directly with the Arf-responsive, PIP2-dependent phospholipase D1 . Biochemical and Biophysical Research Communications . 235 . 3 . 854–9 . June 1997 . 9207251 . 10.1006/bbrc.1997.6793 . free .
17. Kim JH, Lee SD, Han JM, Lee TG, Kim Y, Park JB, Lambeth JD, Suh PG, Ryu SH . 6 . Activation of phospholipase D1 by direct interaction with ADP-ribosylation factor 1 and RalA . FEBS Letters . 430 . 3 . 231–5 . July 1998 . 9688545 . 10.1016/s0014-5793(98)00661-9 . 36075513 .
18. Genth H, Schmidt M, Gerhard R, Aktories K, Just I . Activation of phospholipase D1 by ADP-ribosylated RhoA . Biochemical and Biophysical Research Communications . 302 . 1 . 127–32 . February 2003 . 12593858 . 10.1016/s0006-291x(03)00112-8 .
19. Cai S, Exton JH . Determination of interaction sites of phospholipase D1 for RhoA . The Biochemical Journal . 355 . Pt 3 . 779–85 . May 2001 . 11311142 . 1221795 . 10.1042/bj3550779 .
20. Lewis JA, Scott SA, Lavieri R, Buck JR, Selvy PE, Stoops SL, Armstrong MD, Brown HA, Lindsley CW . 6 . Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity . Bioorganic & Medicinal Chemistry Letters . 19 . 7 . 1916–20 . April 2009 . 19268584 . 3791604 . 10.1016/j.bmcl.2009.02.057 .