Touch plays a fundamental role in our physical, emotional, and social well-being. From a primary way of conveying emotions to sensory integration, it is crucial for the complex growth of cognitive, emotional, social, and behavioural abilities, especially during the early development of infants and children. Touch allows us to build connections with others, eases pain and stress, and helps us to understand the world around us, providing us with crucial information such as the texture, temperature, and shape of objects.
When sensing any stimuli, such as when the body is being touched, the mechanical signals are transformed into biological responses that help us to adapt to continuously changing environments. This transformation involves a variety of intracellular and molecular processes inside the cells that enable us to perceive and respond to tactile stimuli effectively, converting the physical stimuli into electrical activity. The capacity of cells to sense and transmit mechanical forces depends on the correct assembly, localization, and mechanical properties of the protein complexes in the force transmission pathway. Often, large macromolecular protein complexes form liquid-like condensates in a process akin to phase separation.
Such biomolecular condensates are found in many, if not all, eukaryotic cells, and they play a vital role in various physiological and pathological processes, thus emerging as a promising clinical target. Given the liquid-like nature of these biomolecular condensates, their role in mechanotransduction, that is, any mechanism by which cells convert mechanical stimulus into electrochemical activity, is not clear. Although studies have shown that their material properties can change from liquid to solid over time, there is one remaining question: Can these condensates, with different material properties, have different biological functions?
To address the question, ICFO researchers Drs. Neus Sanfeliu, Frederic Català, Iris Ruider, Montserrat Porta and Stefan Wieser, led by Prof. Michael Krieg, in collaboration with IRB Barcelona researchers Drs. Borja Mateos, Carla Garcia, Maria Ribera and Adrià Canals, led by ICREA Prof. Xavier Salvatella, have published a study in Nature Cell Biology identifying the mechanism by which specific protein condensates transition from liquid to solid states, enabling the stability and transmission of the mechanical forces.
The focus of the study was the MEC-2 protein member of the Stomatin family, which is essential for the membrane mechanics and modulation of the ion channel activity. Sanfeliu and the team found that MEC-2 also forms condensates in the touch receptor neurons of the roundworm Caenorhabditis elegans, a model organism widely used for studying the structure and function of the nervous system.
The researchers created transgenic animals carrying a single copy of the MEC-2 protein marked with a fluorescent label. By combining fluorescence imaging in an inverted confocal microscope and the FRAP technique (a fluorescence microscopy method), they identified two distinct MEC-2 populations within touch receptor neurons, namely a liquid and mobile pool, close to the cell body, that facilitates transport along the thin neurons, and a solid-like mature population in distal neurites. They applied mechanical stimuli to the animal’s body wall using a hybrid microfluidic-pneumatic device, in combination with the FRET fluorescence microscopy technique used to study molecular interactions, and observed that only mature populations sustain mechanical forces during touch.
To analyse the properties of these protein condensates, the researchers reproduced the condensation process in the test tube and performed nuclear magnetic resonance experiments, revealing the molecular mechanisms that lead to condensation and regulate the mechanical properties of the condensates. In addition, by using a technique called optical tweezer microrheology, they studied how the mechanical properties of the purified protein condensates changed over time.
With the help of a neuron-specific screen, Sanfeliu and colleagues identified that another protein, UNC-89 from the Titin superfamily, was responsible for promoting MEC-2 condensates rigidity maturation in vivo. This structural transformation led to a shift in their biological function, which switched from facilitating the transport of the protein to facilitating the integration and conversion of mechanical cues during mechanosensation.
These findings describe a new biological function of the liquid-to-solid phase transition of MEC-2 proteins. Furthermore, they also reveal a previously unidentified role for the UNC-89 proteins in neurons.
Given the significant roles that biological condensates play in various physiological and pathological processes, a better understanding of their functions might open up new opportunities for innovative therapies and treatments, such as those aimed at understanding the molecular details that drive rigidity transitions in health and disease.
“We are really excited about the role of condensate maturation in mechanotransduction,” says ICFO Prof. Michael Krieg, “and about looking for ways to investigate how defects in protein condensation participate in the development of neurological disorders.“
Dr. Xavier Salvatella concludes, “It has been known for some time that changes in the material properties of condensates can be detrimental and lead to diseases. But this work shows how they can also be functional and be regulated by protein-protein interactions. It has been great to contribute to this discovery and we look forward to continuing to work on this together with our colleagues at ICFO.“
This study exemplifies the successful collaboration between the research groups involved. As Dr. Krieg says, “We look forward to continued collaboration with Dr. Salvatella’s research group at IRB Barcelona in the hopes of finding new amazing results that can further help us understand cell mechanical properties at the molecular and systems level, to tackle health and disease issues.”
Image: From left to right: researchers Prof. Xavier Salvatella, Carla Garcia and Prof. Michael Krieg (standing); Borja Mateos, Neus Sanfeliu and Federic Català (seated) (ICFO)
Related article: A rigidity phase transition of Stomatin condensates governs a switch from transport to mechanotransduction
Neus Sanfeliu-Cerdán, Frederic Català-Castro, Borja Mateos, Carla Garcia-Cabau, Maria Ribera, Iris Ruider, Montserrat Porta-de-la-Riva, Adrià Canals-Calderón, Stefan Wieser, Xavier Salvatella & Michael Krieg
Nature Cell Biology (2023) DOI: 10.1038/s41556-023-01247-0
About IRB Barcelona
The Institute for Research in Biomedicine (IRB Barcelona) pursues a society free of disease. To this end, it conducts multidisciplinary research of excellence to offer pioneering solutions to unresolved medical needs in cancer and other diseases related to ageing. It establishes technology transfer agreements with the pharmaceutical industry and major hospitals to bring research results closer to society and organises a range of science outreach activities to engage the public in an open dialogue. IRB Barcelona is an international centre that hosts 400 employees and more than 30 nationalities. Recognised as a Severo Ochoa Centre of Excellence since 2011, IRB Barcelona is a CERCA centre and member of the Barcelona Institute of Science and Technology (BIST).
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