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Article ; Online: The role of N-terminal phosphorylation of DGK-θ.

Barbernitz, Millie X / Devine, Lauren R / Cole, Robert N / Raben, Daniel M

2024 Volume 65, Issue 3, Page(s) 100506

Abstract: Diacylglycerol kinases (DGKs) are lipid kinases that mediate the phosphorylation of diacylglycerol (DAG) leading to the production of phosphatidic acid (PtdOH). To examine the role of phosphorylation on DGK-θ, we first identified the phosphorylated sites ...

Abstract	Diacylglycerol kinases (DGKs) are lipid kinases that mediate the phosphorylation of diacylglycerol (DAG) leading to the production of phosphatidic acid (PtdOH). To examine the role of phosphorylation on DGK-θ, we first identified the phosphorylated sites on endogenous DGK-θ from mouse brain and found four sites: S15, S17, which we refer to phosphomotif-1 sites, and S22 and S26 which we refer to as phosphomotif-2 sites. This study focused on the role of these phosphorylated sites on enzyme activity, membrane binding, thermal stability, and cellular half-life of DGK-θ. After generating a construct devoid of all non-catalytic phosphorylation sites (4A), we also generated other constructs to mimic phosphorylation of these residues by mutating them to glutamate (E). Our data demonstrate that an increase in membrane affinity requires the phosphorylation of all four endogenous sites as the phosphomimetic 4E but not other phosphomimietics. Furthermore, 4E also shows an increase in basal activity as well as an increase in the Syt1-induced activity compared to 4A. It is noteworthy that these phosphorylations had no effect on the thermal stability or cellular half-life of this enzyme. Interestingly, when only one phosphorylation domain (phosphomotif-1 or phosphomotif-2) contained phosphomimetics (S15E/S17E or S22E/S26E), the basal activity was also increased but membrane binding affinity was not increased. Furthermore, when only one residue in each domain mimicked an endogenous phosphorylated serine (S15E/S22E or S17E/S26E), the Syt1-induced activity as well as membrane binding affinity decreased relative to 4A. These results indicate that these endogenous phosphorylation sites contribute differentially to membrane binding and enzymatic activity.
MeSH term(s)	Animals ; Mice ; Phosphorylation ; Diglycerides/metabolism ; Diacylglycerol Kinase/genetics ; Diacylglycerol Kinase/metabolism
Chemical Substances	Diglycerides ; Diacylglycerol Kinase (EC 2.7.1.107)
Language	English
Publishing date	2024-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1016/j.jlr.2024.100506
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Article ; Online: NHE3 activity is dependent on direct phosphoinositide binding at the N terminus of its intracellular cytosolic region.

Mohan, Sachin / Tse, Chung Ming / Gabelli, Sandra B / Sarker, Rafiquel / Cha, Boyoung / Fahie, Kamau / Nadella, Mythili / Zachos, Nicholas C / Tu-Sekine, Becky / Raben, Daniel / Amzel, L Mario / Donowitz, Mark

The Journal of biological chemistry

2010 Volume 285, Issue 45, Page(s) 34566–34578

Abstract: The small intestinal BB Na(+)/H(+) antiporter NHE3 accounts for the majority of intestinal sodium and water absorption. It is highly regulated with both postprandial inhibition and stimulation sequentially occurring. Phosphatidylinositide 4,5- ... ...

Abstract	The small intestinal BB Na(+)/H(+) antiporter NHE3 accounts for the majority of intestinal sodium and water absorption. It is highly regulated with both postprandial inhibition and stimulation sequentially occurring. Phosphatidylinositide 4,5-bisphosphate (PI(4,5)P(2)) and phosphatidylinositide 3,4,5-trisphosphate (PI(3,4,5)P(3)) binding is involved with regulation of multiple transporters. We tested the hypothesis that phosphoinositides bind NHE3 under basal conditions and are necessary for its acute regulation. His(6) proteins were made from the NHE3 C-terminal region divided into four parts as follows: F1 (amino acids 475-589), F2 (amino acids 590-667), F3 (amino acids 668-747), and F4 (amino acids 748-832) and purified by a nickel column. Mutations were made in the F1 region of NHE3 and cloned in pet30a and pcDNA3.1 vectors. PI(4,5)P(2) and PI(3,4,5)P(3) bound only to the NHE3 F1 fusion protein (amino acids 475-589) on liposomal pulldown assays. Mutations were made in the putative lipid binding region of the F1 domain and studied for alterations in lipid binding and Na(+)/H(+) exchange as follows: Y501A/R503A/K505A; F509A/R511A/R512A; R511L/R512L; R520/FR527F; and R551L/R552L. Our results indicate the following. 1) The F1 domain of the NHE3 C terminus has phosphoinositide binding regions. 2) Mutations of these regions alter PI(4,5)P(2) and PI(3,4,5)P(3) binding and basal NHE3 activity. 3) The magnitude of serum stimulation of NHE3 correlates with PI(4,5)P(2) and PI(3,4,5)P(3) binding of NHE3. 4) Wortmannin inhibition of PI3K did not correlate with PI(4,5)P(2) or PI(3,4,5)P(3) binding of NHE3. Two functionally distinct phosphoinositide binding regions (Tyr(501)-Arg(512) and Arg(520)-Arg(552)) are present in the NHE3 F1 domain; both regions are important for serum stimulation, but they display differences in phosphoinositide binding, and the latter but not the former alters NHE3 surface expression.
MeSH term(s)	Amino Acid Substitution ; Androstadienes/pharmacology ; Animals ; Cytosol/metabolism ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; Humans ; Mutation, Missense ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphatidylinositols/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Protein Binding ; Protein Kinase Inhibitors/pharmacology ; Protein Structure, Tertiary ; Rabbits ; Rats ; Sodium-Hydrogen Exchanger 3 ; Sodium-Hydrogen Exchangers/genetics ; Sodium-Hydrogen Exchangers/metabolism ; Wortmannin
Chemical Substances	Androstadienes ; Phosphatidylinositols ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors ; SLC9A3 protein, human ; Slc9a3 protein, rat ; Sodium-Hydrogen Exchanger 3 ; Sodium-Hydrogen Exchangers ; Wortmannin (XVA4O219QW)
Language	English
Publishing date	2010-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.165712
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Article ; Online: New therapies for Pompe disease: are we closer to a cure?

Puertollano, Rosa / Raben, Nina

The Lancet. Neurology

2021 Volume 20, Issue 12, Page(s) 973–975

MeSH term(s)	Enzyme Replacement Therapy ; Glycogen Storage Disease Type II/drug therapy ; Humans
Language	English
Publishing date	2021-11-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2081241-3
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(21)00358-6
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Article ; Online: Intravital imaging of muscle damage and response to therapy in a model of Pompe disease.

Meena, Naresh K / Ng, Yeap / Randazzo, Davide / Weigert, Roberto / Puertollano, Rosa / Raben, Nina

Clinical and translational medicine

2024 Volume 14, Issue 3, Page(s) e1561

MeSH term(s)	Humans ; Glycogen Storage Disease Type II/diagnostic imaging ; Glycogen Storage Disease Type II/drug therapy ; Diagnostic Imaging ; Intravital Microscopy ; Muscles
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Intramural ; Comment
ZDB-ID	2697013-2
ISSN	2001-1326 ; 2001-1326
ISSN (online)	2001-1326
ISSN	2001-1326
DOI	10.1002/ctm2.1561
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Article ; Online: AAV-mediated delivery of secreted acid α-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice.

Meena, Naresh K / Randazzo, Davide / Raben, Nina / Puertollano, Rosa

JCI insight

2023 Volume 8, Issue 16

Abstract: Gene therapy is under advanced clinical development for several lysosomal storage disorders. Pompe disease, a debilitating neuromuscular illness affecting infants, children, and adults with different severity, is caused by a deficiency of lysosomal ... ...

Abstract	Gene therapy is under advanced clinical development for several lysosomal storage disorders. Pompe disease, a debilitating neuromuscular illness affecting infants, children, and adults with different severity, is caused by a deficiency of lysosomal glycogen-degrading enzyme acid α-glucosidase (GAA). Here, we demonstrated that adeno-associated virus-mediated (AAV-mediated) systemic gene transfer reversed glycogen storage in all key therapeutic targets - skeletal and cardiac muscles, the diaphragm, and the central nervous system - in both young and severely affected old Gaa-knockout mice. Furthermore, the therapy reversed secondary cellular abnormalities in skeletal muscle, such as those in autophagy and mTORC1/AMPK signaling. We used an AAV9 vector encoding a chimeric human GAA protein with enhanced uptake and secretion to facilitate efficient spread of the expressed protein among multiple target tissues. These results lay the groundwork for a future clinical development strategy in Pompe disease.
MeSH term(s)	Child ; Mice ; Humans ; Animals ; alpha-Glucosidases/genetics ; Glycogen Storage Disease Type II/genetics ; Glycogen Storage Disease Type II/therapy ; Glycogen Storage Disease Type II/pathology ; Dependovirus/genetics ; Dependovirus/metabolism ; Genetic Vectors/genetics ; Mice, Knockout ; Glycogen/metabolism
Chemical Substances	alpha-Glucosidases (EC 3.2.1.20) ; Glycogen (9005-79-2)
Language	English
Publishing date	2023-08-22
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.170199
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Article ; Online: Pompe Disease: New Developments in an Old Lysosomal Storage Disorder.

Meena, Naresh K / Raben, Nina

Biomolecules

2020 Volume 10, Issue 9

Abstract: Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. ... ...

Abstract	Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) which aims to halt the natural course of the illness. Both the success and limitations of ERT provided novel insights in the pathophysiology of the disease and motivated the scientific community to develop the next generation of therapies that have already progressed to the clinic.
MeSH term(s)	Autophagy/genetics ; Enzyme Replacement Therapy/methods ; Genetic Therapy/methods ; Glycogen/metabolism ; Glycogen Storage Disease Type II/enzymology ; Glycogen Storage Disease Type II/genetics ; Glycogen Storage Disease Type II/therapy ; Humans ; Lysosomal Storage Diseases/enzymology ; Lysosomal Storage Diseases/genetics ; Lysosomal Storage Diseases/therapy ; Lysosomes/metabolism ; Muscle, Skeletal/metabolism ; alpha-Glucosidases/deficiency ; alpha-Glucosidases/genetics ; alpha-Glucosidases/therapeutic use
Chemical Substances	Glycogen (9005-79-2) ; alpha-Glucosidases (EC 3.2.1.20)
Language	English
Publishing date	2020-09-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom10091339
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Article: Lipid Metabolism Crosstalk in the Brain: Glia and Neurons.

Barber, Casey N / Raben, Daniel M

Frontiers in cellular neuroscience

2019 Volume 13, Page(s) 212

Abstract: Until recently, glial cells have been considered mainly support cells for neurons in the mammalian brain. However, many studies have unveiled a variety of glial functions including electrolyte homeostasis, inflammation, synapse formation, metabolism, and ...

Abstract	Until recently, glial cells have been considered mainly support cells for neurons in the mammalian brain. However, many studies have unveiled a variety of glial functions including electrolyte homeostasis, inflammation, synapse formation, metabolism, and the regulation of neurotransmission. The importance of these functions illuminates significant crosstalk between glial and neuronal cells. Importantly, it is known that astrocytes secrete signals that can modulate both presynaptic and postsynaptic function. It is also known that the lipid compositions of the pre- and post-synaptic membranes of neurons greatly impact functions such as vesicle fusion and receptor mobility. These data suggest an essential lipid-mediated communication between glial cells and neurons. Little is known, however, about how the lipid metabolism of both cell types may interact. In this review, we discuss neuronal and glial lipid metabolism and suggest how they might interact to impact neurotransmission.
Language	English
Publishing date	2019-05-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2019.00212
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Article ; Online: Roles of DGKs in neurons: Postsynaptic functions?

Barber, Casey N / Raben, Daniel M

Advances in biological regulation

2019 Volume 75, Page(s) 100688

Abstract: Diacylglycerol kinases (DGKs) contribute to an important part of intracellular signaling because, in addition to reducing diacylglycerol levels, they generate phosphatidic acid (PtdOH) Recent research has led to the discovery of ten mammalian DGK ... ...

Abstract	Diacylglycerol kinases (DGKs) contribute to an important part of intracellular signaling because, in addition to reducing diacylglycerol levels, they generate phosphatidic acid (PtdOH) Recent research has led to the discovery of ten mammalian DGK isoforms, all of which are found in the mammalian brain. Many of these isoforms have studied functions within the brain, while others lack such understanding in regards to neuronal roles, regulation, and structural dynamics. However, while previously a neuronal function for DGKθ was unknown, it was recently found that DGKθ is required for the regulation of synaptic vesicle endocytosis and work is currently being conducted to elucidate the mechanism behind this regulation. Here we will review some of the roles of all mammalian DGKs and hypothesize additional roles. We will address the topic of redundancy among the ten DGK isoforms and discuss the possibility that DGKθ, among other DGKs, may have unstudied postsynaptic functions. We also hypothesize that in addition to DGKθ's presynaptic endocytic role, DGKθ might also regulate the endocytosis of AMPA receptors and other postsynaptic membrane proteins.
MeSH term(s)	Animals ; Diacylglycerol Kinase/genetics ; Diacylglycerol Kinase/metabolism ; Endocytosis ; Humans ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Mice ; Neurons/enzymology ; Phosphatidic Acids/genetics ; Phosphatidic Acids/metabolism ; Receptors, AMPA/genetics ; Receptors, AMPA/metabolism ; Synaptic Membranes/enzymology ; Synaptic Membranes/genetics ; Synaptic Vesicles/enzymology ; Synaptic Vesicles/genetics
Chemical Substances	Isoenzymes ; Phosphatidic Acids ; Receptors, AMPA ; Diacylglycerol Kinase (EC 2.7.1.107)
Language	English
Publishing date	2019-11-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2667413-0
ISSN	2212-4934 ; 2212-4926
ISSN (online)	2212-4934
ISSN	2212-4926
DOI	10.1016/j.jbior.2019.100688
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Article: NHE3 Activity Is Dependent on Direct Phosphoinositide Binding at the N Terminus of Its Intracellular Cytosolic Region

Journal of biological chemistry. 2010 Nov. 5, v. 285, no. 45

2010

Abstract: The small intestinal BB Na⁺/H⁺ antiporter NHE3 accounts for the majority of intestinal sodium and water absorption. It is highly regulated with both postprandial inhibition and stimulation sequentially occurring. Phosphatidylinositide 4,5-bisphosphate ( ... ...

Abstract	The small intestinal BB Na⁺/H⁺ antiporter NHE3 accounts for the majority of intestinal sodium and water absorption. It is highly regulated with both postprandial inhibition and stimulation sequentially occurring. Phosphatidylinositide 4,5-bisphosphate (PI(4,5)P₂) and phosphatidylinositide 3,4,5-trisphosphate (PI(3,4,5)P₃) binding is involved with regulation of multiple transporters. We tested the hypothesis that phosphoinositides bind NHE3 under basal conditions and are necessary for its acute regulation. His₆ proteins were made from the NHE3 C-terminal region divided into four parts as follows: F1 (amino acids 475-589), F2 (amino acids 590-667), F3 (amino acids 668-747), and F4 (amino acids 748-832) and purified by a nickel column. Mutations were made in the F1 region of NHE3 and cloned in pet30a and pcDNA3.1 vectors. PI(4,5)P₂ and PI(3,4,5)P₃ bound only to the NHE3 F1 fusion protein (amino acids 475-589) on liposomal pulldown assays. Mutations were made in the putative lipid binding region of the F1 domain and studied for alterations in lipid binding and Na⁺/H⁺ exchange as follows: Y501A/R503A/K505A; F509A/R511A/R512A; R511L/R512L; R520/FR527F; and R551L/R552L. Our results indicate the following. 1) The F1 domain of the NHE3 C terminus has phosphoinositide binding regions. 2) Mutations of these regions alter PI(4,5)P₂ and PI(3,4,5)P₃ binding and basal NHE3 activity. 3) The magnitude of serum stimulation of NHE3 correlates with PI(4,5)P₂ and PI(3,4,5)P₃ binding of NHE3. 4) Wortmannin inhibition of PI3K did not correlate with PI(4,5)P₂ or PI(3,4,5)P₃ binding of NHE3. Two functionally distinct phosphoinositide binding regions (Tyr⁵⁰¹-Arg⁵¹² and Arg⁵²⁰-Arg⁵⁵²) are present in the NHE3 F1 domain; both regions are important for serum stimulation, but they display differences in phosphoinositide binding, and the latter but not the former alters NHE3 surface expression.
Language	English
Dates of publication	2010-1105
Size	p. 34566-34578.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: Editorial for focused issue "Pompe disease: from basics to current and emerging therapies".

Puertollano, Rosa / Raben, Nina

Annals of translational medicine

2019 Volume 7, Issue 13, Page(s) 275

Language	English
Publishing date	2019-08-01
Publishing country	China
Document type	Journal Article
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm.2019.05.57
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