Vaccinia virus, the virus that served as the vaccine to eradicate smallpox, is studied extensively as a model for virus-host interactions, as it employs a whole arsenal of mechanisms to interfere with the hosts immune system. Of its almost 200 genes only half encode proteins required for viral replication. Many of the other genes encode proteins such as A46 that directly interfere with the immune system of the infected organism. “We knew that A46 interacted with several players of the immune system, but the mechanisms of interaction of A46 with its targets has remained unclear”, explains group leader Tim Skern.
Applying electron microscopy, structural biology, and protein crosslinking techniques, PhD student Daniel Azar and Master’s student Meryl Haas now show that A46 destroys assemblies formed by two proteins called MyD88 and MAL. These intracellular adaptor proteins dock to receptors in the cell membrane and relay immune signals to the nucleus where antiviral gene expression is activated. Both proteins are known to form cable-like filaments that transduce these signals. Filament formation of MyD88 and MAL is driven by the interaction of their TIR domains.
The researchers identified the patches in A46 that target the TIR domains of MyD88 and MAL. Based on their experimental findings, the scientists propose that A46 intercalates into the filaments formed by the host proteins and thereby disrupts the signaling chain. “This is an unusual mechanism for viral proteins as it retains the basic structure and function of the host proteins”, says Tim Skern. “More commonly, host proteins are cleaved by the pathogen, rendering them useless”. Moreover, A46 exerts its destructive force in a concentration dependent manner. At lower ratios of A46 to MAL or MyD88, the protein affects filaments by chopping and unwinding them. At higher concentrations of A46, filament assemblies are completely destroyed.
Viruses have a genome ranging from only a few to hundreds of genes, yet manage to propagate and even take over organisms with a much larger genome. “How they manage to do so is a fundamental question in virology that my lab has been tackling for years. Our study now provides insight into a previously unknown mechanism of signaling inhibition.” concludes Tim Skern.
"Science Flash" presentation by first author Daniel Azar explaining the findings.
Original Publication:
Daniel F. Azar, Meryl Haas, Sofiya Fedosyuk, Md. Habibur Rahaman, Andrew Hedger, Bostjan Kobe and Tim Skern: Vaccinia virus immunomodulator A46: Destructive interactions with MAL and MyD88 shown by negative-stain EM
https://www.cell.com/structure/fulltext/S0969-2126(20)30332-4
Profiling and programming in vitro human neuronal diversity at single-cell resolution
18th Microsymposium on RNA Biology
The „Microsymposium on RNA Biology“ is an international conference that brings together young scientists, junior and senior group leaders, and company representatives from all over the world to present and discuss their latest findings in the exciting field of small RNAs and beyond. The Microsymposium was founded in 2005 and has established itself as the major small RNA meeting in Europe. It is organized by the four research institutions IMBA, IMP, GMI and the Max Perutz Labs as well as by the RNA community of the Vienna BioCenter.
Transformation Reactions of Organic Contaminants and Oxygen: From Field Sites to Reaction Mechanisms
Title to be announced
Multiscale plant bioimaging using advanced microscopy
Parthenogenesis, cryptobiosis, and the survival in extreme environmental conditions
Evading ageing: Mitochondrial and proteostatic adaptations in oocytes
Genomes in Rhodnius prolixus symbiotic system
Stem cells, immune evasion and metastasis in colorectal cancer
Ubiquitin & Friends Symposium 2024
The Ubiquitin & Friends Symposium is an annual international meeting taking place in the beautiful capital of Austria, aiming to bring together scholars from various fields studying ubiquitin/Ubl biology and protein degradation in a personal, family-like atmosphere, as suggested by the name.
The evolution and development of mollusc shells
Unraveling the Complexity of Crossover Regulation in C. elegans
Dynamics of 3D Genome Structure and Function
How superworms can help to solve our plastic waste crisis
New players in an old pathway: biology of methanogens of the TACK superphylum
Shaping morphogen gradients: from molecules to tissues and back
Studying stressed cells by in situ structural biology
Exploring Microbial Resilience: Unravelling Escherichia coliand#x27;s Stress Response at the Level of Protein Synthesis
Arbuscular mycorrhiza development and function
Deep homology and deep diversity: Evolving genetic toolkits for making and sensing light
The evolution of cell type identity and tissue microecology at the fetal-maternal interface
The unanticipated roles of PICIs and phages in bacterial evolution
Chemical targeting of subcellular protein localization
Origin and diversification of gut-derived organs in chordates
Job's Dilemma for the Genome: Why Bad Things Happen to Good Chromosomes
Connections between carbon and nitrogen cycling in the ocean
Understanding how the DNA-loop-extruding protein complex Condensin folds a chromatinized genome into mitotic chromosomes
From Roads to Rivers? Occurrence and environmental fate of tire and road wear particles and of tire-related chemicals
FENS 2024 Satellite event: Home cage behavior monitoring at the interface of animal welfare and neuroscience
Striking physiology and cell biology of (marine) environmental microorganisms
Mechanisms controlling maintenance of cohesin dependent loops
Title to be announced