Contrasting functions of ATP hydrolysis by MDA5 and LGP2 in viral RNA sensing
J Biol Chem. 2024 Feb 1:105711. doi: 10.1016/j.jbc.2024.105711. Online ahead of print.
ABSTRACT
Cytosolic long double-stranded RNA (dsRNA), among the most potent proinflammatory signals, is recognized by MDA5. MDA5 binds dsRNA cooperatively, forming helical filaments. ATP hydrolysis by MDA5 fulfills a proofreading function by promoting dissociation of shorter endogenous dsRΝΑs from MDA5 while allowing longer viral dsRNAs to remain bound leading to activation of interferon-β responses. Here, we show that adjacent MDA5 subunits in MDA5-dsRNA filaments hydrolyze ATP cooperatively, inducing cooperative filament disassembly. Consecutive rounds of ATP hydrolysis amplify the filament footprint, displacing tightly bound proteins from dsRNA. Our electron microscopy and biochemical assays show that LGP2 binds to dsRNA at internal binding sites through noncooperative ATP hydrolysis. Unlike MDA5, LGP2 has low nucleic acid selectivity and can hydrolyze GTP and CTP as well as ATP. Binding of LGP2 to dsRNA promotes nucleation of MDA5 filament assembly resulting in shorter filaments. Molecular modeling identifies an internally bound MDA5-LGP2-RNA complex, with the LGP2 C-terminal tail forming the key contacts with MDA5. These contacts are specifically required for NTP-dependent internal RNA binding. We conclude that NTPase-dependent binding of LGP2 to internal dsRNA sites complements NTPase-independent binding to dsRNA ends, via distinct binding modes, to increase the number and signaling output of MDA5-dsRNA complexes.
PMID:38309507 | DOI:10.1016/j.jbc.2024.105711
Ancient seafloor vents spewed tiny, life-giving minerals into Earth’s early oceans
Their study, published in Science Advances, examined 3.5-billion-year-old rocks from western Australia in previously unseen detail and identified large quantities of a mineral called greenalite, which is thought to have played a role in early biological processes. The researchers also found that the seafloor vents would have seeded the oceans with apatite, a mineral rich in the life-essential element phosphorus.
The earliest lifeforms we know of—single-celled microorganisms, or microbes—emerged around 3.7 billion years ago. Most of the rocks that contain traces of them and the environment they lived in have, however, been destroyed. Some of the only evidence we have of this pivotal time comes from an outcrop of sediments in the remote Australian outback.
The so-called Dresser Formation has been studied for years but, in the new study, researchers re-examined the rocks in closer detail, using high magnification electron microscopes to reveal tiny minerals that were essentially hidden in plain sight.
The greenalite particles they observed measured just a few hundred nanometres in size—so small that they would have been washed over thousands of kilometres, potentially finding their way into a range of environments where they may have kick-started otherwise unfavourable chemical reactions, such as those involved in building the first DNA and RNA molecules.
“We’ve found that hydrothermal vents supplied trillions upon trillions of tiny, highly-reactive greenalite particles, as well as large quantities of phosphorus,” said Professor Birger Rasmussen, lead author of the study from the University of Western Australia.
Rasmussen said scientists are still unsure as to the exact role of greenalite in building primitive cells, “but this mineral was in the right place at the right time, and also had the right size and crystal structure to promote the assembly of early cells.”
The rocks the researchers studied contain characteristic layers of rusty-red, iron-rich jasper which formed as mineral-laden seawater spewed from hydrothermal vents. Scientists had thought the jaspers got their distinctive red colour from particles of iron oxide which, just like rust, form when iron is exposed to oxygen.
But how did this iron oxide form when Earth’s early oceans lacked oxygen? One theory is that photosynthesising cyanobacteria in the oceans produced the oxygen, and that it wasn’t until later, around 2.4 billion years ago, that this oxygen started to skyrocket in the atmosphere.
The new results change that assumption, however, “the story is completely different once you look closely enough,” said study co-author Professor Nick Tosca from Cambridge’s Department of Earth Sciences.
The researchers found that tiny, drab, particles of greenalite far outnumbered the iron oxide particles which give the jaspers their colour. The iron oxide was not an original feature, discounting the theory that they were formed by the activity of cyanobacteria.
“Our findings show that iron wasn’t oxidised in the oceans; instead, it combined with silica to form tiny crystals of greenalite,” said Tosca. “That means major oxygen producers, cyanobacteria, may have evolved later, potentially coinciding with the soar in atmospheric oxygen during the Great Oxygenation Event.”
Birger said that more experiments are needed to identify how greenalite might facilitate prebiotic chemistry, “but it was present in such vast quantities that, under the right conditions its surfaces could have synthesized an enormous number of RNA-type sequences, addressing a key question in origin of life research – where did all the RNA come from?”
Reference:
Rasmussen, B., Muhling, J., Tosca, N.J. 'Nanoparticulate apatite and greenalite in oldest, well-preserved hydrothermal vent precipitates.' Science Advances (2024). DOI: 10.1126/sciadv.adj4789
Researchers from the universities of Cambridge and Western Australia have uncovered the importance of hydrothermal vents, similar to underwater geysers, in supplying minerals that may have been a key ingredient in the emergence of early life.
MARUM − Zentrum für Marine Umweltwissenschaften, Universität BremenThe hydrothermal vent "Candelabra" in the Logatchev hydrothermal field on the Mid-Atlantic Ridge at a water depth of 3300 m
The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.
Identification of Campylobacter jejuni and Campylobacter coli genes contributing to oxidative stress response using TraDIS analysis
BMC Microbiol. 2024 Feb 1;24(1):46. doi: 10.1186/s12866-024-03201-y.
ABSTRACT
BACKGROUND: Campylobacter jejuni and Campylobacter coli are the major causative agents of bacterial gastroenteritis worldwide and are known obligate microaerophiles. Despite being sensitive to oxygen and its reduction products, both species are readily isolated from animal food products kept under atmospheric conditions where they face high oxygen tension levels.
RESULTS: In this study, Transposon Directed Insertion-site Sequencing (TraDIS) was used to investigate the ability of one C. jejuni strain and two C. coli strains to overcome oxidative stress, using H2O2 to mimic oxidative stress. Genes were identified that were required for oxidative stress resistance for each individual strain but also allowed a comparison across the three strains. Mutations in the perR and ahpC genes were found to increase Campylobacter tolerance to H2O2. The roles of these proteins in oxidative stress were previously known in C. jejuni, but this data indicates that they most likely play a similar role in C. coli. Mutation of czcD decreased Campylobacter tolerance to H2O2. The role of CzcD, which functions as a zinc exporter, has not previously been linked to oxidative stress. The TraDIS data was confirmed using defined deletions of perR and czcD in C. coli 15-537360.
CONCLUSIONS: This is the first study to investigate gene fitness in both C. jejuni and C. coli under oxidative stress conditions and highlights both similar roles for certain genes for both species and highlights other genes that have a role under oxidative stress.
PMID:38302896 | PMC:PMC10832277 | DOI:10.1186/s12866-024-03201-y
Swarming cicadas, stock traders, and the wisdom of the crowd
Pick almost any location in the eastern United States – say, Columbus Ohio. Every 13 or 17 years, as the soil warms in springtime, vast swarms of cicadas emerge from their underground burrows singing their deafening song, take flight and mate, producing offspring for the next cycle.
This noisy phenomenon repeats all over the eastern and southeastern US as 17 distinct broods emerge in staggered years. In spring 2024, billions of cicadas are expected as two different broods – one that appears every 13 years and another that appears every 17 years – emerge simultaneously.
Previous research has suggested that cicadas emerge once the soil temperature reaches 18°C, but even within a small geographical area, differences in sun exposure, foliage cover or humidity can lead to variations in temperature.
Now, in a paper published in the journal Physical Review E, researchers from the University of Cambridge have discovered how such synchronous cicada swarms can emerge despite these temperature differences.
The researchers developed a mathematical model for decision-making in an environment with variations in temperature and found that communication between cicada nymphs allows the group to come to a consensus about the local average temperature that then leads to large-scale swarms. The model is closely related to one that has been used to describe ‘avalanches’ in decision-making like those among stock market traders, leading to crashes.
Mathematicians have been captivated by the appearance of 17- and 13-year cycles in various species of cicadas, and have previously developed mathematical models that showed how the appearance of such large prime numbers is a consequence of evolutionary pressures to avoid predation. However, the mechanism by which swarms emerge coherently in a given year has not been understood.
In developing their model, the Cambridge team was inspired by previous research on decision-making that represents each member of a group by a ‘spin’ like that in a magnet, but instead of pointing up or down, the two states represent the decision to ‘remain’ or ‘emerge’.
The local temperature experienced by the cicadas is then like a magnetic field that tends to align the spins and varies slowly from place to place on the scale of hundreds of metres, from sunny hilltops to shaded valleys in a forest. Communication between nearby nymphs is represented by an interaction between the spins that leads to local agreement of neighbours.
The researchers showed that in the presence of such interactions the swarms are large and space-filling, involving every member of the population in a range of local temperature environments, unlike the case without communication in which every nymph is on its own, responding to every subtle variation in microclimate.
The research was carried out Professor Raymond E Goldstein, the Alan Turing Professor of Complex Physical Systems in the Department of Applied Mathematics and Theoretical Physics (DAMTP), Professor Robert L Jack of DAMTP and the Yusuf Hamied Department of Chemistry, and Dr Adriana I Pesci, a Senior Research Associate in DAMTP.
“As an applied mathematician, there is nothing more interesting than finding a model capable of explaining the behaviour of living beings, even in the simplest of cases,” said Pesci.
The researchers say that while their model does not require any particular means of communication between underground nymphs, acoustical signalling is a likely candidate, given the ear-splitting sounds that the swarms make once they emerge from underground.
The researchers hope that their conjecture regarding the role of communication will stimulate field research to test the hypothesis.
“If our conjecture that communication between nymphs plays a role in swarm emergence is confirmed, it would provide a striking example of how Darwinian evolution can act for the benefit of the group, not just the individual,” said Goldstein.
This work was supported in part by the Complex Physical Systems Fund.
Reference:
R.E. Goldstein, R.L. Jack, and A.I. Pesci. ‘How Cicadas Emerge Together: Thermophysical Aspects of their Collective Decision-Making.’ Physical Review E (2024). DOI: 10.1103/PhysRevE.109.L022401
The springtime emergence of vast swarms of cicadas can be explained by a mathematical model of collective decision-making with similarities to models describing stock market crashes.
Ed Reschke via Getty ImagesAdult Periodical Cicada
The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.
Wed 07 Feb 14:00: What is still so fascinating about the trypanosome coat?
The cell surface coat of African trypanosomes has been studied for a long time. So you could assume that all the essentials are known. However, this is not the case. In my talk, I focus on the fabric from which this coat is woven (the VGSs) and their incredible dynamics. We’ve known for 20 years that the VSG coat can be recycled quickly, and we have a good idea of why. However, how the underlying biological processes can take place at such high speeds is only gradually coming to light. We’re trying to put the puzzle together step by step. In doing so, we sometimes come across surprising insights that can shed new light on basic cell biology. That’s what I’m going to tell you about. In addition, I would like to make my talk a plea for continuing research into parasitic protozoa, whose extreme adaptations can expand our reductionist perspective on cell biology.
- Speaker: Prof Markus Engstler - Universität Wüerzburg - Germany
- Wednesday 07 February 2024, 14:00-15:00
- Venue: Seminar Room, Tennis Court Road, Dept of Pathology..
- Series: Parasitology Seminars; organiser: Anna Protasio.
Wed 07 Feb 14:00: What is still so fascinating about the trypanosome coat?
The cell surface coat of African trypanosomes has been studied for a long time. So you could assume that all the essentials are known. However, this is not the case. In my talk, I focus on the fabric from which this coat is woven (the VGSs) and their incredible dynamics. We’ve known for 20 years that the VSG coat can be recycled quickly, and we have a good idea of why. However, how the underlying biological processes can take place at such high speeds is only gradually coming to light. We’re trying to put the puzzle together step by step. In doing so, we sometimes come across surprising insights that can shed new light on basic cell biology. That’s what I’m going to tell you about. In addition, I would like to make my talk a plea for continuing research into parasitic protozoa, whose extreme adaptations can expand our reductionist perspective on cell biology.
- Speaker: Prof Markus Engstler - Universität Wüerzburg - Germany
- Wednesday 07 February 2024, 14:00-15:00
- Venue: Seminar Room, Tennis Court Road, Dept of Pathology..
- Series: Parasitology Seminars; organiser: Anna Protasio.
Temporal dynamics of the early immune response following Mycobacterium bovis infection of cattle
Sci Rep. 2024 Jan 31;14(1):2600. doi: 10.1038/s41598-024-52314-x.
ABSTRACT
Bovine tuberculosis is an infectious disease of global significance that remains endemic in many countries. Mycobacterium bovis infection in cattle is characterized by a cell-mediated immune response (CMI) that precedes humoral responses, however the timing and trajectories of CMI and antibody responses determined by newer generation assays remain undefined. Here we used defined-antigen interferon-gamma release assays (IGRA) and an eleven-antigen multiplex ELISA (Enferplex TB test) alongside traditional tuberculin-based IGRA and IDEXX M. bovis antibody tests to assess immune trajectories following experimental M. bovis infection of cattle. The results show CMI responses developed as early as two-weeks post-infection, with all infected cattle testing positive three weeks post-infection. Interestingly, 6 of 8 infected animals were serologically positive with the Enferplex TB assay as early as 4 weeks post-infection. As expected, application of the tuberculin skin test enhanced subsequent serological reactivity. Infrequent M. bovis faecal shedding was observed but was uncorrelated with observed immune trajectories. Together, the results show that early antibody responses to M. bovis infection are detectable in some individuals and highlight an urgent need to identify biomarkers that better predict infection outcomes, particularly for application in low-and-middle income countries where test-and-slaughter based control methods are largely unfeasible.
PMID:38297023 | PMC:PMC10831113 | DOI:10.1038/s41598-024-52314-x