Lipid News

Back to the (poly)basics

Phosphoregulation of lipin enzymes
Salome Boroda Thurl Harris
By Salome Boroda and Thurl Harris
Feb. 1, 2018

Glycerolipid synthesis occurs largely in the endoplasmic reticulum, or ER. Almost all the enzymes involved in making glycerolipids are embedded in the membranes of the ER. The exception is a family of enzymes called lipins, which dephosphorylate phosphatidic acid, or PA, to generate diacylglycerol in the penultimate step of glycerolipid synthesis.

Lipins are soluble proteins that can be found in the cell cytosol but can move to the ER membrane to perform their function. This family of enzymes consists of three members known as lipins 1-3. Genetic studies have shown that increased levels of lipin 1 in the fat tissue of transgenic mice can improve glucose homeostasis, and genetic mutations in human lipins 1 and 2 have been associated with diseases such as rhabdomyolysis, a rapid destruction of skeletal muscle cells, and Majeed syndrome, a rare condition characterized by recurrent episodes of fever and inflammation in the bones and skin. At the molecular level, a series of studies has demonstrated a complex regulation of the lipin family that is tied intimately to their phosphorylation state and the chemical properties of PA (1-4).

The substrate of lipins can exist in two electrostatic forms: it is either monoanionic (-1 charged) or dianionic (-2 charged) (5). When the membrane pH rises or when PA is in proximity to hydrogen bond donors — such as phosphatidylethanolamine (PE) — it exists as a dianionic compound. All lipin family members preferentially associate with dianionic PA; this can be observed as an increase in lipin activity and association with PA in the presence of PE (2-5). And while it has been known that the lipins are highly phosphorylated, it is now becoming clear how phosphorylation might affect lipin enzymatic activity (2-4). Specifically, phosphorylation negatively regulates the ability of lipin 1 to associate with, and act against, dianionic PA (2). However, the activities of lipins 2 and 3 are not affected by their phosphorylation state (3, 4). Why such a stark difference in molecular regulation of enzymes that catalyze the same reaction? Perhaps the answer lies within lipins themselves.

A schematic of lipin polybasic domain exchange mutants. Salome Baroda/University of Virginia

All lipins contain a polybasic domain, or PBD, a short nine-amino acid sequence composed of lysines and arginines that is responsible for lipin association with PA (6). The precise sequence and number of lysines versus arginines varies between the lipins. Recent work has revealed that the unique PBD of lipin 1 may be the reason it is subject to regulation by its phosphorylation (phosphoregulation) (4). The evidence for this came from studies where the lipin 1 PBD was replaced with the PBD from lipin 3. When the activity of this mutant lipin was measured, it was found that the presence of the lipin 3 PBD eliminated the phosphoregulation of the lipin 1 enzyme.

Conversely, the specific activity of the lipin 3 mutant containing the lipin 1 PBD showed potent inhibition by phosphorylation. While it is possible that the mutant lipin proteins became dysregulated, phosphoproteomic analysis found no significant changes compared to their wild-type counterparts.

To date, there is no structural information available for lipins. As such, the mechanisms whereby lipin 1 phosphorylation interferes with the ability of the lipin 1 PBD to recognize dianionic PA are a matter of speculation. However, the variation in the molecular regulation of lipins suggests that each has a unique role in specific cellular stimuli and physiological conditions, and perhaps the field is just beginning to elucidate the true complexity behind the function of these enzymes. Further work is needed to probe exactly how these enzymes may be regulated post-translationally. In particular, the exact residues and molecular pathways involved in the negative phosphoregulation of lipin 1 are still unknown and could provide insight into its physiological role.

References

1. Harris, T.E. et al. J. Biol. Chem. 282, 277-286 (2007).

2. Eaton, J.M. et al. J. Biol. Chem. 288, 9933-9945 (2013).

3. Eaton, J.M. et al. J. Biol. Chem. 289, 18055-18066 (2014).

4. Boroda, S. et al. J. Biol. Chem. 292, 20481-20493 (2017).

5. Shin, J.J. & Loewen, C.J. BMC Biol. 9, 85-7007-9-85 (2011).

6. Ren, H., et al. Mol. Biol. Cell. 21, 3171-3181 (2010).

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Salome Boroda
Salome Boroda

Salome Boroda is a research associate for clinical studies at the University of Virginia School of Medicine, in the department of anesthesiology.

Thurl Harris
Thurl Harris

Thurl Harris is an associate professor of pharmacology at the University of Virginia.

Related articles

At the interface
Lina M. Obeid & Michael J. Pulkoski-Gross
Unexpected roles of lipid kinases
Kaoru Goto & Toshiaki Tanaka
Cholesterol lures in coronavirus
Marissa Locke Rottinghaus
Lipids, lipids everywhere!
Michael Airola & Robert V. Stahelin

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Simple trick could improve accuracy of plant genetics research
News

Simple trick could improve accuracy of plant genetics research

June 16, 2024

Researchers at North Carolina State University have found that a technique used to study gene activity in other organisms can also be used to make studies in plants more accurate.

Scientists track 'doubling' in origin of cancer cells
News

Scientists track 'doubling' in origin of cancer cells

June 15, 2024

Researchers at Johns Hopkins say they have charted a molecular pathway that can lure cells down a hazardous path of duplicating their genome too many times.

From the journals: JBC
Journal News

From the journals: JBC

June 14, 2024

Ribosomal RNA, R-loops and the RNA exosome. Using an old drug to treat a new skin disease, Sugar-binding immune receptors. Read about recent papers on these topics.

New gene new strides in gangliosidosis
Journal News

New gene new strides in gangliosidosis

June 11, 2024

A gene that decreases disease progression in mice provides a new direction for human therapy.

Brushing with bacteria: The debate over a GMO tooth microbe
News

Brushing with bacteria: The debate over a GMO tooth microbe

June 9, 2024

One startup has said a genetically modified microbe could prevent cavities. Experts, though, have safety concerns.

Newly discovered genetic variant clarifies why Parkinson’s develops
News

Newly discovered genetic variant clarifies why Parkinson’s develops

June 8, 2024

Researchers at the University of Florida have found that the mutation called RAB32 Ser71Arg both causes the condition and could show how to halt it.