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From the journals: JBC

Marissa Locke Rottinghaus
May 31, 2024

A novel antiviral factor fights flu. Clamping onto DNA. Glycosylation ensures healthy bones. Read about articles on these topics recently published in the Journal of Biological Chemistry.

 

Novel antiviral factor fights flu

The Centers for Disease Control and Prevention estimates that influenza virus makes more than 10 million sick per year in the U.S. During viral infection, the innate immune system is the first line of defense. This system comprises nonspecific receptors that recognize pathogen-associated molecular patterns. Activation of these receptors triggers downstream signaling cascades that drive expression or activation of antiviral factors, such as antiviral gene interferon-induced transmembrane protein 3, or IFITM3.

National Institute of Allergy and Infectious Diseases/Wikimedia Commons

Despite more than 50 years of research, scientists know little about the effectors that regulate innate immunity. Therefore, Moiz Munir of the University of Texas Southwestern Medical Center and U.S. collaborators performed a genome-wide CRISPR–Cas9 activation screen to identify novel antiviral genes. They found a novel antiviral factor, JADE3, and published their results in the Journal of Biological Chemistry.

Most CRISPR–Cas9 screens used to identify antiviral effectors have focused on loss-of-function phenotypes. However, the researchers used a new approach, CRISPR activation, or CRISPRa, to identify factors that antagonize influenza in cultured HeLa cells. After the CRISPRa screen, they identified 10 novel genes that, when activated, conferred resistance to influenza infection. The team further investigated the candidate JADE3, since other researchers recently showed it can inhibit SARS-CoV-2 and norovirus infection. JADE3 is a member of a family that drives histone H4 acetylation, which regulates gene transcription. However, neither JADE1 nor JADE2 could protect against influenza infection, indicating that JADE3 possesses unique functions. After performing RNA sequencing and Western blots, the researchers found that JADE3 induces expression of IFITM3, an antiviral molecule important for restricting influenza, via nuclear factor kappa-light-chain-enhancer of activated B cells, or NF-κB.

This study provides novel insight into the factors that regulate viral infection and could help researchers create antivirals that augment expression of JADE3. Future studies will investigate the molecular mechanism by which JADE3 regulates NF-κB.

 

Clamping onto DNA

DNA replication requires clamp loaders, to open and load ring-shaped sliding clamps onto DNA. DNA polymerases tether to DNA-bound sliding clamps to rapidly synthesize DNA. To load sliding clamps, clamp loaders first bind adenosine nucleotide triphosphate, or ATP, which enables them to bind and open sliding clamps. Next, the open clamp loader sliding clamp complex binds to DNA, which triggers ATP hydrolysis and the clamp loader to dissociate, leaving the sliding clamp wrapped around DNA. DNA polymerases can then bind to the sliding clamp and synthesize DNA. However, scientists do not yet know the precise mechanism by which bacterial clamp loaders bind to, open and load the sliding clamps onto DNA. Therefore, Jacob Landeck of the University of Massachusetts Chan Medical School and colleagues investigated the structure of E. coli clamp loaders using cryogenic electron microscopy and compared the mechanism of clamp loading between bacteria and eukaryotes. Their results were published in the Journal of Biological Chemistry.

They found that bacterial and eukaryotic clamp loaders use distinct mechanisms to open their sliding clamps. The E. coli clamp loader opens its sliding clamp through a single pivot point into a planar arrangement. Conversely, the eukaryotic clamp loader uses motion distributed across the protein to open its sliding clamp into a helical conformation. Upon binding DNA, the E. coliclamp loader sliding clamp complex adopts a helical arrangement and the mechanisms of bacterial and eukaryotic clamp loaders converge through the initiation of clamp release. These studies highlight that, though clamp loading is conserved, eukaryotes and prokaryotes have distinct structural mechanisms. These findings could be used to aid the design of novel antibiotics that target prokaryotic clamp loaders.

 

Glycosylation ensures healthy bones

O-linked glycosylation is an essential posttranslational modification carried out by glycosyltransferase enzymes known as GALNTs, which catalyze the transfer of the sugar group N-acetylgalactosamine, or GalNAc, onto serine and threonine residues of proteins. The mammalian GALNT family consists of more than 20 members, and deficiencies in individual members, such as GALNT2 and GALNT3, cause severe disease. However, scientists do not yet fully understand the functions of all GALNT proteins. Therefore, E Tian and a team at the National Institute of Dental and Craniofacial Research, National Institutes of Health investigated the role of Galnt11 in mice on vitamin D homeostasis and bone composition.

The authors previously observed that mice lacking Galnt11 reabsorbed less vitamin D. In this study, published in the Journal of Biological Chemistry, they showed that Galnt11-deficient mice have lower vitamin D and calcium as well as increased parathyroid hormone at baseline. Next, the authors evaluated the musculoskeletal system of mice genetically altered to lack Galnt11 and found that they have abnormally short femurs and higher rates of bone turnover. These results provide insight into the effects of GALNT11 mutations on skeletal homeostasis in humans and may lead to targeted therapeutics that boost vitamin D in these patients.

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Marissa Locke Rottinghaus

Marissa Locke Rottinghaus is the science writer for the ASBMB.

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