From the journals

Published November 01 2017

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.

 

Genetic vulnerability to drugs prescribed for mental illness

Between 1 percent and 3 percent of humans carry at least one defective DHCR7 gene, which produces the enzyme responsible for the final step in cholesterol production in many cell types. People with two defective DHCR7 genes have a condition known as Smith-Lemli-Opitz syndrome. The syndrome can be mild (with physical abnormalities and learning and behavioral problems) or severe (with profound intellectual disability and life-threatening physical defects). But being only a carrier of a defective DHCR7 gene also carries risks. A new study in the Journal of Lipid Research reports that defective DHCR7 carriers may face undesired effects from the commonly prescribed antipsychotic drug aripiprazole (marketed as Abilify) and the antidepressant trazodone (marketed as Oleptro and other brand names). Researchers led by Ned A. Porter at Vanderbilt University tested the drugs on human fibroblasts and observed significant, dose-dependent increases in 7-DHC levels. This was consistent with a 2013 report that found the drugs can elevate 7-DHC levels in those with and without Smith-Lemli-Opitz syndrome. The authors wrote: “We argue that in the era of precision medicine, potential differences in response to compounds that disrupt the cholesterol biosynthesis pathway must be respected, especially as their effect may be defined by both genetic makeup and life events at the same time.” The authors note that there are 33 other known drugs that affect 7-DHC levels, “so the studies reported here may point to a problem of broad scope.”

Treating Parkinson’s with a parasite drug

The anti-helminth drug nitazoxanide has off-target effects on mitochondrial respiration. Niharika Amireddy of the Indian Institute of Chemical Technology and colleagues examined the effect of nitazoxanide on mice treated with a neurotoxin to induce Parkinson’s disease symptoms, which include effects on mitochondrial function. In a paper in the Journal of Biological Chemistry, they report that nitazoxanide ameliorated apoptosis and neuron loss in these mice, suggesting that this drug potentially could be repurposed to treat Parkinson’s disease.

Demystifying virus-host interactions

When a virus enters a host cell, its genome interacts with a myriad of host factors to promote viral gene expression, DNA replication and virion assembly. Identifying these interacting host factors can provide insights into the critical regulatory steps during the infectious process. To do this, a team led by Matthew Weitzman of the University of Pennsylvania crosslinked the host factors of infected human cells with the DNA of adenovirus, herpes simplex virus and vaccinia virus. The viral DNA was purified along with the bound host factors, which subsequently were identified using mass spectrometry. The investigators uncovered a number of host factors that were deactivated by early viral proteins and identified a subgroup of nucleolar proteins that aid virus replication. The comprehensive databases generated in this study, published in Molecular & Cellular Proteomics, provide valuable resources for probing virus-host interactions.

Tracing signals in developing teeth

As organs develop, growth factors and other signaling molecules often are produced from clusters of specialized cells called signaling centers. Wei Du of Sichuan University and colleagues used developmental lineage tracing to identify the origins of signaling centers in developing teeth. As reported in a recent paper in the Journal of Biological Chemistry, they found that signaling centers in molars and incisors are formed by two distinct mechanisms, one involving de novo assembly of signaling centers and the other involving progeny from previously established signaling centers.

Document your storage methods — and preserve your HDL!

Researchers at the Medical University of Graz in Austria evaluated 100 research papers sourced from PubMed using the search terms “HDL ultracentrifugation” and “HDL proteome” and found that the majority — 64, to be precise — said absolutely nothing about how the HDL used in the experiments had been stored. Led by Michael Holzer at the Institute of Experimental and Clinical Pharmacology, the research team went on to determine that “prolonged freezing at -20°C or -70°C led to a shedding of apolipoprotein-AI from HDL and to the formation of large protein-poor particles, indicating that HDL is irreversibly disrupted.” The team also reported in the Journal of Lipid Research that using sucrose or glycerol, both cryoprotectants, could preserve the structure and function of HDL for at least two years. Flash freezing, often used to store tissues, was not protective, however. They wrote: “HDL is a complex particle requiring special attention when stored. The use of cryoprotectants will improve the reproducibility and quality of the research data obtained.” Bottom line: Do yourself and science a favor by employing cryoprotectants and recording your methods.

Weekend feasts do a number on triglyceride levels

There are plenty of reasons to hate Mondays. Now you can add triglycerides to the list. A recent study in the Journal of Lipid Research reports that our Monday triglyceride counts may reveal our lazy, food-filled weekends. A research team led by Jörn Jaskolowski at the University of Copenhagen took a look at 1.8 million blood samples from patients in Denmark and found that workweek triglyceride levels are highest on Mondays and then gradually subside through Friday. This was true for both children and adults, which reduces the likelihood that alcohol intake is a significant factor. The authors note that high triglyceride levels are seen in patients with metabolic syndrome, so they are tracked in various research projects. “(C)areful planning of future studies may help to avoid undesirable differences attributed to the day and
the time of the day the measurement was obtained,” they wrote.

A bacterial protease that manipulates blood clotting

Bacterial sepsis often is complicated by improperly regulated blood clotting, and it is thought that pathogens can protect themselves from the immune system by hiding in blood clots. Giulia Pontarollo and colleagues at the University of Padua provide new support for this hypothesis in their report in the Journal of Biological Chemistry that subtilisin, a serine protease secreted by Bacillus subtilis, is able to activate the human coagulation-promoting enzyme thrombin through a different mechanism than that used by human cells to activate it.

A novel virulence factor in Salmonella

Salmonella typhimurium is a bacterial pathogen that can cause a wide spectrum of diseases, from intestinal inflammation to typhoid fever. It delivers its virulence factors, also termed effector proteins, to infected cells via two type III secretion systems, SPI-1 and SPI-2. In a study in Molecular & Cellular Proteomics, Xiaoyun Liu and colleagues at Peking University applied quantitative secretome profiling to catalogue the effector proteins delivered by SPI-1. They identified a novel effector, which they named SopF, that they showed to be toxic to host cells and important in intracellular replication. The study underscores the utility of a quantitative secretome profiling strategy in identifying novel bacterial virulence factors.

Cancer-related protein Notch requires rare sugar modification

Modifying proteins with sugars increases the diversity of protein structures and functions. In contrast to other types of glycosylation, O-linked modifications with glucose and fucose affect only a small number of proteins, including the essential signaling receptor Notch. Hideyuki Takeuchi of the University of Georgia and colleagues used CRISPR/Cas-based knockout of the enzymes responsible for these modifications to show that they were necessary for Notch transport to the cell membrane. In a recent paper in the Journal of Biological Chemistry, they write that fucose and glucose were attached only to Notch EGF repeats in their folded form, suggesting that these modifications serve as a quality-control mechanism for Notch folding.

Advancing glycoproteomics analysis

Glycosylation is among the most abundant and diverse protein posttranslational modifications, regulating important cellular processes such as protein folding and cell-cell interactions. High-throughput identification of glycans by mass spectrometry remains challenging due to the limited number of computational programs available to analyze the vast complexity of glycan structure and composition. In a study in Molecular & Cellular Proteomics, Sriram Neelamegham and colleagues at the University of Buffalo introduced an open-source computational framework called GlycoPAT to address this limitation. GlycoPAT includes advances in glycan identification, scoring schemes and false discovery–rate calculation. Using GlycoPAT, the investigators identified 960 unique glycopeptides from prostate cancer cells.

How iron maintains checks and balances

Iron is essential for many proteins to function, but excess iron is toxic to cells. Accordingly, cells have finely tuned regulatory systems for controlling iron levels. IRP-1 is an mRNA-binding protein that represses the expression of various proteins involved in iron homeostasis. When intracellular iron is high, IRP-1 is inactivated by the insertion of an iron-sulfur cluster. In a recent paper in the Journal of Biological Chemistry, Nathan Johnson and colleagues at the University of Wisconsin-Madison write that they found that IRP-1 activity also could be suppressed by degradation when the iron-sulfur cluster biogenesis system was disabled, and that there were regulatory feedbacks between the protein degradation and iron-sulfur cluster mechanisms.

A mysterious mosquito protein

Understanding insect development and physiology is important for developing strategies to control vector-borne diseases such as malaria and dengue fever. Juvenile hormone regulates development and reproduction in arthropods. Il Hwan Kim of the National Institutes of Health and colleagues discovered a protein of unknown function that specifically binds juvenile hormone in several species of mosquito. A recent paper in the Journal of Biological Chemistry describes how they found that this protein was structurally similar to mosquito salivary proteins important for parasite transmission during blood feeding, but that it was present in the hemolymph of both male and female adult mosquitoes.

Heartfelt signals from the z-disc

The z-disc is a structure involved in the contraction of cardiac and skeletal muscle, and mutations in z-disc proteins are associated with heart and muscle diseases. In a recent paper in the Journal of Biological Chemistry, Franziska Dierck of the University Medical Center of Schleswig-Holstein and colleagues write that they identified a previously uncharacterized z-disc protein named CEFIP upregulated in cardiomyopathy. CEFIP bound to proteins in the calcineurin signaling pathway and enhanced calcineurin-dependent signal transduction, suggesting a mechanism for its involvement in pathology.

Sasha Mushegian Sasha Mushegian is scientific communicator for JBC.

Angela Hopp Angela Hopp is executive editor of ASBMB Today and communications director for the ASBMB.

Saddiq Zahari Saddiq Zahari is a postdoctoral scholar at the University of California, San Francisco, and the editor for manuscript integrity at MCP.