Journal News

From the journals: JBC

Anand Rao
Sept. 21, 2020

We offer a selection of papers on a variety of topics recently published in the Journal of Biological Chemistry. Topics include proteases that fire up the flu, a sulfate pocket to take out MRSA and proteins that prompt cancer protrusions.

Pinpointing the proteases that make flu go viral

There are four main types of influenza viruses — A, B, C and D — and nearly every winter in the U.S. the influenza A and B viruses cause the disease epidemic known as flu season. Globally, influenza A and B account for over 300,000 deaths and 3 million to 5 million cases of severe respiratory illness each year, according to the World Health Organization.

Influenza-890x904.jpg
Centers for Disease Control Influenza Laboratory
Researchers are studying the proteases responsible for cleaving the influenza A and B glycoprotein hemagglutinin, found in viruses such as H1N1 influenza, shown here in a colorized image.

Hemagglutinin, or HA, is a glycoprotein located on the surface of influenza viruses. HA is activated by cleavage by host cell proteases and is essential for initiating the entry of influenza virus into host cells. Understanding the mechanisms of HA protein cleavage is important for development of flu therapies, but the proteases involved in the activation of many viral strains remain unknown.

In a recent paper published in the Journal of Biological Chemistry, Anne Harbig of Philipps-University Marburg and an international team revealed a collection of proteases that process HA and govern protease functionality against specific HA glycoproteins. Using RNA sequencing, infection of mouse cell lines and plaque assay analysis, the authors analyzed the collection of proteases present in mouse lower airway tissues and identified four candidate proteases responsible for influenza A and B HA activation: hepsin, prostasin and two transmembrane serine proteases, or TMPRSSs, known as TMPRSS4 and TMPRSS13.

The researchers used protease inhibitors alongside transfection of TMPRSS13, hepsin and prostasin in double-knockout Tmprss2-/-Tmprss4-/- cells to identify differences in HA reliance on protease cleavage. They found that HA proteases overlap in the two influenza viruses but demonstrate functional differences. Finally, the authors extended their work from mouse airway tissue to human tissue, finding that human orthologs of hepsin and prostasin cleave influenza B HA extensively but not influenza A HA.

The researchers’ data suggest that influenza A and B strains have overlapping sets of proteases that cleave HA differently and that protease activity differs in mice and humans. Identifying the factors responsible for influenza HA activation has both basic science and potential therapeutic applications.

Lab-grown amyloidosis model measures up

Systemic amyloidosis is a rare hereditary disorder that commonly manifests in heart, kidney, liver and nerve complications, sometimes leading to organ failure. Systemic amyloidosis is caused by misfolded proteins, such as transthyretin, resisting the body’s catabolic processes and building up outside cells. Studies seeking to identify the biological mechanisms underlying this condition require clinically relevant disease models.

In recent work published in the Journal of Biological Chemistry, Sara Raimondi of the University of Pavia and an international team compared the characteristics of fibrils generated experimentally with natural transthyretin fibrils to assess their value as a model for systemic amyloidosis. The authors found that the experimentally generated fibrils are thermodynamically and structurally similar to naturally occurring amyloid fibrils.

These results show that laboratory-grown transthyretin fibrils are a useful model for investigating the pathophysiology of amyloidosis.

Sorting sensor domains to unearth MRSA enzyme inhibitors

Infections by methicillin-resistant Staphylococcus aureus, or MRSA, bacteria are notoriously difficult to treat due to the bacteria’s resistance to several antibiotics. Contributing to MRSA’s antibiotic resistance are two integral membrane proteins, BlaR1 and MecR1.

In a recent paper published in the Journal of Biological Chemistry, J. Andrew N. Alexander of the University of British Columbia and colleagues at the University of Maryland and San Francisco General Hospital solved the X-ray crystallographic structures of the BlaR1 and MecR1 sensor domains in complex with avibactam, a beta-lactamase inhibitor that blocks the activity of the beta-lactamase enzyme produced by S. aureus.

These findings reveal the presence of a secondary sulfate-binding pocket that could be exploited in the design of future inhibitors capable of treating MRSA.

Ribosomes don’t rewire protein folding reactions

To function properly, proteins must adopt and maintain specific conformations. They typically reach their final structure by cycling through preferred intermediate conformations, a process that starts during protein synthesis. But how the ribosome affects protein folding remains unclear.

Using a ribosomal force-profiling assay, Madeleine Jensen of the University of California, Berkeley, and collaborators at the University of Cambridge showed that ribosomal interactions have little impact on the folding pathways of RNase H, suggesting that the ribosome does not influence protein folding. Additionally, the authors found that the ribosome promotes RNase H unfolding while the growing protein chain is close to the ribosome, which may limit the detrimental effects of RNase H misfolding and assist in folding fidelity.

These results, reported in a recent paper in the Journal of Biological Chemistry, provide new insights into how ribosomes affect the folding of nascent proteins.

Adaptor protein prompts cancer cell membrane protrusion

Invadopodia — protrusions from the membranes of cancer cells that are rich in the cytoskeletal protein actin — are essential for metastasis. The role of transforming growth factor beta, or TGF-beta, in metastasis has been well established, but how TGF-beta signaling is linked to cancer cell motility as well as its relation to invadopodia remain unknown.

Alex Kiepas of McGill University and collaborators at Laval University revealed that Src-homology/collagen adaptor protein initiates the dynamic adhesion complexes necessary for invadopodium formation in a TGF-beta–dependent manner.

These findings, published in a recent study in the Journal of Biological Chemistry, further researchers’ understanding of cancer metastasis and open new avenues for cancer drug discovery.

Anand Rao

Anand Rao is an ASBMB science communicator.

Related articles

From the journals: March 2019
John Arnst, Courtney Chandler, Isha Dey & Catherine Goodman
Robert L. Post (1920 – 2021)
Jack H. Kaplan, Paul J. DeWeer & Joseph F. Hoffman
From the journals: MCP
Kian Kamgar-Parsi

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Part 1: ‘Aha moments’ essay contest honorable mentions
Contest

Part 1: ‘Aha moments’ essay contest honorable mentions

May 6, 2021

To celebrate our three journals going open access, we invited readers to share their moments of discovery in science. Here are two honorable mentions.

From the journals: MCP
Journal News

From the journals: MCP

May 6, 2021

Using silver nanoparticles to target cancer. Glycosylation of SARS-CoV-2. Characterizing the glycan signature in tumor tissue. Read about recent papers in the journal Molecular & Cellular Proteomics.

Ceramides’ role in liver disease
Lipid News

Ceramides’ role in liver disease

May 5, 2021

These biologically active sphingolipids have roles in apoptosis, inflammation and insulin resistance, all critical factors in the pathogenesis of chronic liver disease.

Winners of the ‘aha moments’ essay contest
Contest

Winners of the ‘aha moments’ essay contest

May 4, 2021

To celebrate our three journals going open access, we invited readers to share their moments of discovery in science. Here are the first, second and third place winners.

The 17th-century cloth merchant who discovered the vast realm of tiny microbes
News

The 17th-century cloth merchant who discovered the vast realm of tiny microbes

May 2, 2021

Although untrained in science, Antonie van Leeuwenhoek became the greatest lens-maker of his day, discovered microscopic life forms and is known today as the “father of microbiology.”

Do kids really need to be vaccinated for COVID?
News

Do kids really need to be vaccinated for COVID?

May 1, 2021

Many experts argue that Covid-19 cannot be curbed without vaccinating children. But others aren’t so sure.