NIMBB Researchers Uncover RNA-Binding Proteins as Potential Key Players in Tardigrade Immune Response

Tardigrades, known colloquially as water bears, have long intrigued scientists with their ability to withstand extreme conditions, from freezing temperatures to intense radiation and even the vacuum of space. But beyond surviving environmental extremes, these microscopic organisms also face the constant threat of infection posed by their surrounding microbial community which includes fungi and bacteria. These biological interactions with potential pathogens intuitively suggest that tardigrades possess an immune system. While we know a lot about the immune systems of other animals, how tardigrades mount immune responses to protect themselves from harmful microorganisms remain unknown.

In an ongoing study, NIMBB researchers uncovered novel insights into the immune system of Mesobiotus philippinicus, the first limnoterrestrial water bear species discovered in the Philippines. This study builds upon earlier findings from Mapalo et al., 2020 that hinted at how tardigrades use a modified version of a well-known immune signaling pathway called the Toll pathway.

What is the Toll Signaling Pathway?

Understanding the Toll signaling pathway is helpful in appreciating the importance of this study. The Toll pathway is essential to the immunological response of many animals that acts like an alarm system. Briefly, the detection of an invading pathogen causes the Toll receptor on the surface of immune cells to trigger a cascade of events inside the cell that ultimately results in the activation of genes that help combat the infection.

In well-studied organisms like fruit flies and humans, the Toll pathway is well understood, involving several downstream proteins that transmit the signal. However, in tardigrades, the story is different. While they possess the Toll receptor, tardigrades lack the typical proteins that would normally help carry the signal forward. Interestingly, Mapalo et al. (2020) identified genes in tardigrades coding for components of other immune pathways. More importantly, however, they found that both the Toll receptor and its corresponding ligand were active in M. philippinicus, strengthening the hypothesis that tardigrades do indeed rely on a version of the Toll pathway as part of their immune response.This led scientists including NIMBB researchers to ask: how do tardigrades use the Toll pathway to defend themselves against pathogens if they are missing key components of this pathway?

Mining Active Genes in Tardigrades 

To answer the previous question, NIMBB researchers from the Protein Structure and Immunology Laboratory set out to find proteins in M. philippinicus that might be involved in the Toll signaling pathway. But instead of looking for proteins that are exact matches to those found in other animals, the team used a different approach. They looked for small, specific sequences within proteins—known as motifs—that are critical for binding to the Toll receptor.

Using this innovative approach, the researchers discovered three proteins relevant to the Toll pathway that could be key players in the tardigrade’s immune response. However, unlike the typical Toll pathway components in other animals, these proteins turned out to be RNA-binding proteins. According to Ms. Karen E. Joson, the first author of the study, “These Toll-binding proteins having an RNA-binding ability could suggest that they participate in RNA processing, which implies a role in controlling gene expression.” This previously unknown mechanism of immune response may provide tardigrades with a unique way of managing infections.

Implications of the Findings: Why It Matters

This discovery opens new possibilities for understanding how tardigrades control their immune responses. The presence of these RNA-binding proteins in the Toll pathway of tardigrades suggests that in tardigrades, the Toll signaling pathway might lead to changes in RNA processing, which could then affect how genes are turned on or off in response to an infection. This unique mechanism could be a more streamlined way of regulating the immune response: “In terms of evolution, these results might illustrate the way an organism that might tend to undergo extensive gene loss, as has been seen for other gene families, might adapt to maintain its immune response while probably having less genes,” Ms. Joson said, highlighting the evolutionary significance of this finding.

Looking Ahead: What’s Next?

While the study has provided valuable insights, the researchers acknowledge that there is a lot more to explore and uncover in the immune system of tardigrades by further improving their approach. Since the search for motif-containing proteins was somewhat restricted by the methods available at the time, the researchers are interested in refining their methods to identify more potential players in the tardigrade immune system.

Moving forward, the team plans to conduct molecular dynamics simulations to see how these proteins behave in motion. This could provide even more detailed information about how they interact with RNA and the Toll receptor, further illuminating the unique immune strategies of these highly resilient organisms.