A comparison of immune proteins called viperins from Asgard archaea (left) and from a group of more complex life that includes humans, called eukaryotes (right). The three-dimensional shapes (a.k.a. structures) are strikingly similar, suggesting they also function similarly.
Credit: Pedro Leão.
Multicellular organisms are collections of specialised eukaryote cells, which are themselves collections of prokaryote cells that have been around for several billion years before getting together to form more complex cells.
And those prokaryote cells - bacteria and archaea - had had to cope with viruses which arose as soon as there were replicating assemblages of DNA for them to parasitize and co-opt the replication mechanism to make more copies of themselves.
The result was one of the first evolutionary arms races as the prokaryotes evolved ways to prevent themselves being parasitised and viruses evolved ways to overcome the microbes defences.
And, or course, the later eukaryote, complex cells that were to form the multicellular organisms inherited these antiviral defences and carried on the arms race with viruses, so it makes sense to find some of the remnants of these microbial defences, probably modified, inside our own cells, and forming a first line of defences.
This is a simple prediction of the Theory of Evolution and the resulting descent with modification from a common ancestor from billions of years ago.
What information do you have on the anti-viral proteins, Asgard Viperin and Eukaryote Viperin?
Asgard Viperin and Eukaryote Viperin are both antiviral proteins that play crucial roles in the innate immune response, particularly in targeting and neutralizing viral infections. They belong to a broader family of proteins called Viperin (virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible). Viperin is a well-known antiviral protein that is highly conserved across various species, including archaea, bacteria, and eukaryotes. Here's a breakdown of what is known about Asgard Viperin and Eukaryote Viperin:
- Asgard Viperin
- Origin: Asgard Viperin is derived from the Asgard archaea, a group of microorganisms that are thought to be closely related to the last common ancestor of archaea and eukaryotes. These archaea were discovered in deep-sea hydrothermal vent environments and are considered important in studying the evolution of complex life forms.
- Function: Asgard Viperin has been identified as an antiviral protein that provides insights into the ancient mechanisms of immune defense. Its function is similar to that of Viperin in eukaryotes, where it inhibits viral replication by targeting viral components or the cellular machinery viruses depend on for replication.
- Structure and Mechanism: Like other Viperins, Asgard Viperin is likely to have a radical SAM (S-adenosylmethionine) domain, which is critical for its antiviral activity. This domain allows the protein to produce a reactive radical species, which can interfere with viral processes, such as the synthesis of nucleotides that viruses require for replication.
- Evolutionary Significance: The discovery of Asgard Viperin highlights the ancient origins of antiviral defense mechanisms. It suggests that the strategies used by modern eukaryotic cells to combat viruses may have deep evolutionary roots.
- Eukaryote Viperin
- Origin: Eukaryote Viperin is found in eukaryotic organisms, including humans. It is one of the interferon-stimulated genes (ISGs) that are upregulated in response to viral infection. This protein is highly conserved across various species, from simple eukaryotes like algae to complex organisms like mammals.
- Function: In eukaryotes, Viperin is a key player in the innate immune response. It exerts its antiviral effects through multiple mechanisms, depending on the type of virus. For example:
- Inhibition of Viral Replication: Viperin can interfere with the replication of viruses by altering lipid metabolism or disrupting the assembly of viral particles.
- Interaction with Cellular Machinery: It can inhibit viral RNA polymerase, thereby preventing the replication of RNA viruses.
- Modulation of Immune Response: Viperin can enhance the production of other antiviral molecules and modulate the signaling pathways involved in the immune response.
- Mechanism of Action: The radical SAM domain is crucial for the antiviral activity of Viperin in eukaryotes. This domain facilitates the formation of a radical species that can interfere with the function of viral proteins or the host cell machinery that viruses exploit.
- Clinical Relevance: Understanding the role of Viperin in the immune response has significant implications for developing antiviral therapies. Since Viperin is involved in the response to a wide range of viruses, enhancing its activity could be a potential strategy for treating viral infections.
Comparative Insights
- The study of Asgard and Eukaryote Viperin provides valuable insights into the evolution of antiviral defense mechanisms. The presence of similar antiviral proteins in both archaea and eukaryotes suggests that these defense strategies are ancient and have been conserved throughout evolution.
- While both Asgard and Eukaryote Viperin share functional similarities, their specific roles and mechanisms may differ due to the differences in their cellular environments and the types of viruses they encounter.
Research Significance
- The discovery and study of Asgard Viperin contribute to our understanding of the origin of eukaryotic cells and their immune systems. It also opens up new avenues for research into the evolution of antiviral defenses and the development of new antiviral strategies based on ancient mechanisms.
Understanding these proteins, particularly in the context of their evolutionary history and their function in modern organisms, is crucial for advancing our knowledge of immune responses and the development of antiviral therapies.
And this is precisely what researchers in the College of Natural Science at The University of Texas at Austin have found. They have shown that the proteins Asgard Viperin from the Asgard archaea and the Eukaryote viperin, possessed by eukaryotes including humans are structurally (and functionally) very similar.
Next Time You Beat a Virus, Thank Your Microbial Ancestors
Two of our key defenses against viruses have persisted for billions of years, arising before complex life.
When you get infected with a virus, some of the first weapons your body deploys to fight it were passed down to us from our microbial ancestors billions of years ago. According to new research from The University of Texas at Austin, two key elements of our innate immune system came from a group of microbes called Asgard archaea.
Specifically, viperins and argonautes, two proteins that are known to play important roles in the immune systems of all complex life — from insects to plants to humans — came from the Asgard archaea. Versions of these defense proteins are also present in bacteria, but the versions in complex life forms are most closely related to those in Asgard archaea, according to the new scientific study published in the journal Nature Communications.
This research bolsters the idea that all complex life, called eukaryotes, arose from a symbiotic relationship between bacteria and Asgard archaea.
It adds more support to the fact that the Asgards are our microbial ancestors. It says that not only did eukaryotes get all these rich structural proteins that we’ve seen before in Asgards, now it’s saying that even some of the defense systems in eukaryotes came from Asgards.
Associate Professor Brett J. Baker, senior author
Associate professor of integrative biology and marine science
Department of Integrative Biology
University of Texas at Austin, Austin, TX, USA.
The researchers identified for the first time a large arsenal of defense systems in archaea that were previously known only in bacteria.
When viperins detect foreign DNA, which might indicate a dangerous virus, they edit the DNA so that the cell can no longer make copies of the DNA, which stops the virus from spreading. When argonautes detect foreign DNA, they chop it up, also halting the virus. Additionally, in more complex organisms, argonautes can block the virus from making proteins in a process called RNA silencing.
Viral infections are one of the evolutionary pressures that we have had since life began, and it is critical to always have some sort of defense. When bacteria and archaea discovered tools that worked, they were passed down and are still part of our first line of defense.
Assistant Professor Pedro Leão, lead author
Department of Microbiology - RIBES
Radboud University, Nijmegen, The Netherlands.
The researchers compared proteins involved in immunity across the tree of life and found many closely related ones. Then they used an AI tool called ColabFold to predict whether ones that had similar amino acid sequences also had similar three-dimensional shapes (aka structures). (It’s the shape of a protein that determines how it functions.) This showed that variations of the viperin protein probably maintained the same structure and function across the tree of life. They then created a kind of family tree, or phylogeny, of these sister amino acid sequences and structures that showed evolutionary relationships.
A family tree of immune proteins called viperins from different organisms. Versions of viperin found in complex life forms, called eukaryotes (green), fit within the group of viperins from Asgard archaea (purple).
Credit: University of Texas at Austin.
Finally, the researchers took viperins from Asgard archaea genomes, cloned them into bacteria (so the bacteria would express the proteins), challenged the bacteria with viruses, and showed that Asgard viperins do in fact provide some protection to the modified bacteria. They survived better than bacteria without the immune proteins.
This research highlights the integral role cellular defenses must have played from the beginning of both prokaryotic and eukaryotic life. It also inspires questions about how our modern understanding of eukaryotic immunity can benefit from unraveling some of its most ancient origins.
Emily Aguilar-Pine, co-author
Department of Integrative Biology
University of Texas at Austin, Austin, TX, USA.
It’s undeniable at this point that Asgard archaea contributed a lot to the complexity that we see in eukaryotes today, so why wouldn’t they also be involved in the origin of the immune system? We have strong evidence now that this is true.
Assistant Professor Pedro Leão
Other authors, all from UT, are Mary Little, Kathryn Appler, Daphne Sahaya, Kathryn Currie, Ilya Finkelstein and Valerie De Anda.
This work was supported by the Simons and Moore foundations (via the Moore-Simons Project on the Origin of the Eukaryotic Cell) and The Welch Foundation.
Abstract
Dozens of new antiviral systems have been recently characterized in bacteria. Some of these systems are present in eukaryotes and appear to have originated in prokaryotes, but little is known about these defense mechanisms in archaea. Here, we explore the diversity and distribution of defense systems in archaea and identify 2610 complete systems in Asgardarchaeota, a group of archaea related to eukaryotes. The Asgard defense systems comprise 89 unique systems, including argonaute, NLR, Mokosh, viperin, Lassamu, and CBASS. Asgard viperin and argonaute proteins have structural homology to eukaryotic proteins, and phylogenetic analyses suggest that eukaryotic viperin proteins were derived from Asgard viperins. We show that Asgard viperins display anti-phage activity when heterologously expressed in bacteria. Eukaryotic and bacterial argonaute proteins appear to have originated in Asgardarchaeota, and Asgard argonaute proteins have argonaute-PIWI domains, key components of eukaryotic RNA interference systems. Our results support that Asgardarchaeota played important roles in the origin of antiviral defense systems in eukaryotes.
Introduction
Organisms across the tree of life contain complex defense systems (DS) to battle viral infections1,2,3. Over the past decade, dozens of new DS have been identified and characterized in bacteria, sparking a debate about a potential link between these systems and the origins of innate immune mechanisms in eukaryotes. More recently, protein components of bacterial NLR (Nucleotide-binding domain leucine-rich repeat), CBASS (Cyclic oligonucleotide-based antiphage signaling system), viperins (virus-inhibitory protein, endoplasmic reticulum-associated, interferon (IFN)-inducible), argonautes, and other DS have been shown to exhibit homology with proteins involved in the eukaryotic immune system4. Most of the research on prokaryotic defense systems has focused on bacteria, with archaea representing <3% of the genomes in these studies5,6,7. Thus, very little is known about the diversity or evolution of these systems in archaea.
Recently, diverse novel genomes have been obtained belonging to the archaea most closely related to eukaryotes, commonly referred to as “Asgard” archaea, the phylum Asgardarchaeota8. In addition to being sister lineages to eukaryotes, these archaea also contain an array of genes that are hallmarks of complex cellular life involved in signal processing, transcription, and translocations, among other processes9. The Asgard archaea are descendants of the ancestral host that gave rise to eukaryotic life. One newly described order, the Hodarchaeales (within the Heimdallarchaeia class), shared a common ancestor with eukaryotes8. Here, we characterize defense systems in archaea and show that Asgard archaea have a broad array of these DS. We also show that Asgards contributed to the origins of innate immune mechanisms in eukaryotes.
Fig. 2: Evolutionary history and anti-phage activity of Asgard viperins.
A Phylogenetic analysis of viperins. Viperins phylogeny revealed ancestral links of eVip (eukaryotic viperin) with asVip (asgard viperin) (nodes marked in red), particularly those within the Heimdallarchaeia class (including Kariarchaeaceae (2), Heimdallarchaeaceae (3) and Hodarchaeales (5)). The size of the dots on the nodes is proportional to bootstrap values ranging between 60 and 100.
B Structure-based homology of viperins. Consistent with the sequence homology-based phylogenetic tree, the eVip structure appears to have been inherited from asVip (red node). The darker green color represents reference sequences predicted experimentally. The size of the dots at the center of the nodes is proportional to bootstrap values ranging between 50 and 100.
C Superposition of an eVip structure, predicted by X-ray diffraction (green), and the structural models of an asVip, archaeal viperin (arVip), and bacterial viperin (from left to right). The yellow color in the models emphasizes the high conservation of the viperin catalytic site across the tree of life. The information regarding bacteria, archaea, asgard archaea and eukaryotes in panels (
A–C) are represented by the pink, blue, purple and green color respectively.
D Anti-T7 phage activity of asVip in
E. coli. Nine asVip (asVip 26,11,20,25,16,12,17,23,8) exhibited anti-viral activity as indicated by the
p-values (*p < 0.05; **p < 0.01).
E Anti-T7 phage activity of asVip after codon optimization for their expression in
E. coli. One asVip from a Hodarchaeales organism provided protection against viral infection (asVip 19). The center line of each box plot denotes the median; the box contains the 25
th to 75
th percentiles. Black whiskers mark the 5th and 95
th percentiles. pVip34 is a prokaryotic viperin selected as a positive control from Bernheim
et al.
13. Each experimental condition includes, on average, 53 plaques pooled from three biological replicates. A two-tailed t-test was used to calculate statistical significance in figures (
E, D).
Fig. 3: Evolutionary history of Asgard argonaute proteins.
A Phylogeny of long type argonaute proteins from archaea, bacteria, and eukaryotes with cyclases as outgroup (grey). B Structure-based homology of argonautes. C Structural alignment of asAgo5 and 4OLA (eAgo) MID and PIWI domains (left), and the graphic model of the corresponding alignments (right). Salmon regions on the alignment highlight strong conservation (low RMDS values). Red amino acids in the structural alignment, and their respective models represent the 4OLA conserved functional residues in MID and PIWI. The information regarding bacteria, archaea, asgard archaea and eukaryotes are represented by the pink, blue, purple and green color respectively. The size of the dots on the nodes is proportional to bootstrap values ranging between 70 and 100.
A highly-conserved antiviral protein across all eukaryote cells speaks loudly of common ancestry. The fact that a very similar protein is found in an "Asgard" archaea is strongly supportive of the theory that the fist eukaryote cells were alliances of bacteria and archaea and that the "Asgard" archaea contributed antiviral protection on this early eukaryote, showing common ancestry extending back beyond the first eukaryotes.
Of course, the less intelligent creationists will now be chanting 'Common Ancestry', but the more intelligent cultists would realise that that would mean the first eukaryote cells arose
after Adam and Eve, because these antiviral proteins wouldn't have been needed until after 'Sin' had allowed viruses to 'devolve' by 'genetic entropy' (© Michael J. Behe), unless they don't understand how having an arms race with oneself is not the sign of an intelligent designer.
