From the journals: May 2018

We offer a selection of recent papers on a variety of topics from the Journal of Biological Chemistry, the Journal of Lipid Research and Molecular & Cellular Proteomics.

Molecular secrets of bacterial signaling

Cyclic di-adenosine monophosphate is an essential bacterial signaling molecule, the functions of which are still incompletely understood. Angelika Gründling and colleagues at Imperial College London examined the role of c-di-AMP in the pathogen Staphylococcus aureus, which is unable to grow without c-di-AMP in rich medium but able to in minimal medium. Their experiments suggested that c-di-AMP is required for regulating osmolyte intake. Furthermore, they showed that methicillin-resistant S. aureus strains lacking c-di-AMP were hypersensitive to a beta-lactam antibiotic, suggesting that targeting c-di-AMP may be a strategy for treating drug-resistant staph infections. The findings were published in the Journal of Biological Chemistry.

Fatty acid addition lets a parasite stick

Trichomonas vaginalis, commonly known as trich, is the most common curable sexually transmitted disease, and the vast majority of people with the disease — upward of 70 percent — do not experience symptoms, according to the Centers for Disease Control and Prevention. However, the protozoan parasite can increase an infected person’s risk of contracting HIV or developing cancer and can cause preterm labor in pregnant women. In other parasites, a protein modification called palmitoylation, the addition of a 16-carbon saturated fatty acid to cysteine residues of a protein, regulates infectivity. In a new paper in the journal Molecular & Cellular Proteomics, researchers at the Instituto Tecnologico de Chascomus in Buenos Aires and the University of California, Los Angeles, enriched palmitoylated proteins from T. vaginalis and found numerous palmitoylation sites in pathogenesis-related proteins. Yesica Nievas and colleagues report that disrupting palmitoylation reduced the protist’s self-aggregation and adhesion to host cells. This work establishes the importance of palmitoylation in T. vaginalis proteins for infection and suggests that palmitoylation enzyme inhibitors may help treat the infection.

Fat can cause selective insulin resistance

Ordinarily, insulin causes cells in the liver to switch energy sources by turning down the activity of enzymes that make new glucose and increasing the activity of genes that govern lipid synthesis. This switch lets cells store energy when blood glucose is abundant. But in diabetes, a paradox occurs: Insulin fails to shut off gluconeogenesis while still stimulating lipid synthesis. To find out how this phenomenon, called selective insulin resistance, can arise, researchers at Harvard University and the Broad Institute reduced the complexity of the problem by studying the effects of the fatty acid palmitate on insulin signaling in cultured liver cells. The researchers, Zhihuan Li and colleagues, reported in the journal Molecular & Cellular Proteomics that the presence of palmitate increased glycerolipid levels and disrupted a small number of proteins that normally would respond to insulin, including the transcription factors FoxO1 and NFkappaB and the kinase GSK3. The researchers also identified many previously unknown insulin-induced phosphorylation sites. They propose that their comprehensive data set may be useful for generating hypotheses about how insulin signaling is controlled in the more complex environment of the liver.

Primate tau problems

Defects in the protein tau, which is abundant in the central nervous system, are associated with both Alzheimer’s and Parkinson’s disease. The tau protein of primates has an N-terminal motif that is absent in tau from other mammals. Arne Ittner and colleagues at the University of New South Wales investigated whether this region may be responsible for humans’ increased susceptibility to tau-related disorders compared with other animals. They found that this region mediates interactions with several neuronal proteins. Because protein interactions affect tau pathology, this motif may be critical for understanding neurodegenerative diseases. The research was published in the Journal of Biological Chemistry.

A potential oncogene for gastric cancer

Gastric cancer has one of the highest mortality rates among cancers, but its mechanisms and biomarkers remain poorly understood. Zhengsheng Wu and colleagues at Anhui Medical University in China showed that the proline-rich protein GSE1, which previously was known to have an oncogenic role in breast cancer, promotes gastric cancer proliferation, invasion and metastasis both in vitro and in mouse models. Its expression correlated with patterns of survival and relapse in gastric cancer patients. GSE1’s cancer-promoting role appeared to involve the amino acid transporter SLC7A5, which was upregulated when GSE1 stabilized the SLC7A5 transcript. The research was published in the Journal of Biological Chemistry.

Eicosanoid profile in cultured cells

Cultured cells depend on media for many essential nutrients, among them polyunsaturated fatty acids. Researchers observed that cells’ production of signaling lipids derived from PUFAs by cultured macrophages changes over time between media changes as the cells exhaust the available essential PUFAs. In an article in the Journal of Lipid Research, Toshiaki Okuno and colleagues from Jutendo University in Japan and the University of Colorado in Denver quantified the changes to various lipids. In addition to fluctuating lipid levels, they observed that the number of days since the previous media change dramatically altered tumor necrosis factor secretion in response to lipopolysaccharide, an inflammation mediator. The study suggests that cell feeding schedules may introduce variability among in vitro experiments, which could be reduced by flow-through culture.

Phases of aggregation in Huntington’s disease

In Huntington’s disease patients, the huntingtin protein has extended lengths of repeated glutamines at one end, which cause the protein to form neurotoxic aggregates. In a paper in the Journal of Biological Chemistry, Rohit Pappu and colleagues at Washington University in St. Louis found that these aggregates fall into three distinct categories delineated by concentration thresholds, sizes and morphologies. They also found that profilin, an actin-binding protein known to reduce huntingtin aggregation, interacts with aggregates in one specific phase. Understanding the phase behavior of huntingtin and other aggregation-prone proteins may be important for developing therapies.

How calcium pump rates relate to skin health

Darier disease is a rare autosomal dominant disorder of the skin characterized by severe rashes or lesions caused by mutations in a particular isoform of the sarcoendoplasmic reticulum calcium transport ATPase, or SERCA. Jens Peter Andersen and colleagues at Aarhus University in Denmark reported in the Journal of Biological Chemistry that a Darier disease mutation affected the interaction between an isoform-specific cytoplasmic loop and other regions of the protein. This change increased SERCA’s calcium transport rate, which could activate a stress response and induce apoptosis, perhaps explaining its role in Darier disease pathology.