Double-membrane-spanning pore protein for viral replication

Positive-strand RNA viruses, including coronaviruses, have long been known to replicate their genomes within a vesicle wrapped, like the autophagosome, within a double plasma membrane. This raises the question of how newly-copied viral genomes reenter the cytoplasm to be packaged into new viruses. In a recent issue of Science, Wolff and colleagues report having discovered a pore-forming protein that spans both layers of the double-membraned vesicle, offering an escape route. You can read the article or a highlight by Unchwaniwala and Ahlquist..

Gene editing for lipid-linked diseases in macaques

At 2020’s virtual meeting of the International Society for Stem Cell Research, the company Verve Therapeutics announced that it had successfully used CRISPR editing to knock out PCSK9 and ANGPTL3 in the liver of adult monkeys. The modifications, co-founder and CEO Sekar Kathiresan reported, lowered blood triglycerides (in the case of ANGPTL3) or cholesterol (in the case of PCSK9) by more than 50%.

While underlying data have not yet appeared in a journal, you can read the press release here or a report by STAT news here.

How lipid droplets stay in shape

A recent Q&A with Andrew Greenberg in ASBMB Today traces the story behind his lab’s discovery of perilipin.

Perilipin (stained red) binds to the surface of lipid droplets (green) and functions as a dynamic scaffolding protein that controls entry and exit of lipids from the droplets.

While studying lipid droplet metabolsim in adipocytes, Greenberg’s lab discovered that perlipin is a crucial regulator of triglyceride metabolism.

Images in Lipid Research

A mass spectrometry image of the mouse brain shows distribution of different lipid species. Andres et al., JLR 2020

The Journal of Lipid Research recently launched a new article format focused on the contributions of imaging technologies to our understanding of lipid biology. These images in lipid research are brief articles focused on a single figure.

In an editorial introducing the series, associate editor Stephen Young wrote, “We anticipate that JLR’s Images in Lipid Research series will be fun and informative for practicing scientists.”

You can browse the images in lipid research here.

Disrupting sphingolipid synthesis improves mouse neurodegeneration symptoms

In a recent article in the Proceedings of the National Academy of Sciences (PNAS), researchers in the joint lab of Robert Farese and Tobias Walther at the Harvard T.H. Chan School of Public Health & HHMI report a special role for sphingolipids in a mouse model of motor neuron disease.

In wobbler mice, which carry a Golgi-resident protein mutation that impairs membrane trafficking from endosomes into the Golgi apparatus, Constance Petit and colleagues showed that sphingolipids are particularly apt to build up to harmful levels. The defect, the researchers found, likely occurs because of missorting of lysosome proteins into the Golgi. Reducing sphingolipid synthesis ameliorated the symptoms of neurodegeneration.

Allostery in bacterial biosynthesis of a lipid vitamin

While humans depend on dietary sources of menaquinone, or vitamin K2, many bacteria can synthesize their own. Because of this discordance, and because the isoprenoid is used in the bacterial electron transport chain, menaquinone biosynthesis is an appealing potential target for new antimicrobials.

In observance of World Tuberculosis Day, Jodie Johnston of the University of Canterbury in New Zealand wrote in ASBMB Today about her team’s discovery of an allosteric site in the M. tuberculosis enzyme MenD that mediates feedback inhibition in menaquinone biosynthesis. Their paper was selected as an Editor’s Pick in the Journal of Biological Chemistry.

How does allergic contact dermatitis arise?

Classically allergens are peptides, presented by the MHC to a T cell receptor. But most of the molecules that cause contact dermatitis are not peptides. One model to explain this phenomenon is that dermatitis-causing chemicals could bind, covalently or not, to peptides that bind to MHCs, then get presented to T cells. But a new study suggests an alternative, MHC-independent route.

In research appearing in Science Immunology, Nicolai and colleagues screened numerous chemicals for contact allergenicity through CD1, a class of proteins that resemble MHCs in structure and function but have more hydrophobic antigen presentation structures. They found that CD1 can present hydrophobic antigens to T cells, and ordinarily presents lipids from the plasma membrane, such as species of PC, PI, DAG and sphingomyelins. A series of crystal structures shows that “bulky industrial lipids” such as farnesol, which is used in cosmetics and perfumes, appear able to displace these self-lipids. The authors observed differences in response to farnesol among donor T cells that might help explain variations in susceptibility to contact dermatitis. You can read the article here. (open access)

Cell-type-specific deficits in sterol metabolism may contribute to recurrent miscarriage

Progesterone produced by placental tissue plays an important role in early pregnancy. As a steroid hormone, progesterone is produced by conversion of cholesterol through a pregnenolone intermediate. In a recent study in the Journal of Lipid Research, Vondra and colleagues detected differences in cholesterol uptake and progesterone synthesis between cells that remain at the surface of the placenta and those that migrate into the endometrium to direct vascular remodeling. Some preliminary evidence suggests that defects in progesterone synthesis in the latter cell type may contribute to recurrent miscarriage. Read the study here.

High-EPA fish oil derivative approved for cardiovascular disease

The Food and Drug administration has approved Vascepa, a medication derived from fish oil, to treat high triglycerides, which are linked to cardiovascular disease.

Whereas fish oil contains a mix of long-chain omega-3 fatty acids, including eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA), Vascepa, manufactured by Amarin Pharmaceuticals, contains only EPA. According to researchers on the drug’s Phase III study, which was published in the New England Journal of Medicine in January, the drug’s extra benefit compared to fish oil may derive from removing DHA, which has been shown to increase LDL cholesterol.

You can read more on the relative benefits of long-chain omega-3 fatty acids in an open-access editorial by Wolf-Hagen Schunck in the Journal of Lipid Research.