Clusters containing a protein called LAT use specific adapters to move and drive the activation of T-cells to fight off infection, according to a study, the findings of which may help design immune cells with more selective effects, the researchers suggest.
The study, “A composition-dependent molecular clutch between T cell signaling condensates and actin,” was published in the journal eLIFE.
Protein condensates are clusters of different proteins that form inside cells and are involved in processes such as RNA storage, DNA repair, and response to stress. They have been implicated in a variety of diseases, such as amyotrophic lateral sclerosis (ALS), Huntington’s, and several types of cancer.
The composition and function of these condensates are determined by the interactions among protein and RNA scaffolds forming their structure.
These condensates play an important role during the activation of T-cells, which help B-cells produce antibodies and alert the rest of the body when an infection is present. In the immune response, the condensates organize around a protein called the linker for activation of T-cells (LAT) at the junction between the T-cell and the antigen-presenting cell, called the immunological synapse (IS).
A network of filaments within the cell made from a protein called actin continuously guides a condensate carrying LAT from the cell periphery toward the center of the cortex to keep the T-cell activated.
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However, exactly how concentrates containing LAT move across the IS — and the importance of their composition in this process — is not very well understood.
A team from the U.K., U.S., and India addressed this question by analyzing the in vitro interactions between LAT condensates and cellular filaments made of actin. This revealed that LAT condensates bind actin primarily via distinct regions of adapter proteins known as Nck and N-WASP/WASP.
Specifically, Nck was no longer bound to the LAT condensates as it reached the IS. This was associated with a change in actin structure to circular arcs, more notably at the center of the synapse. Use of a mutant form of Grb2, an intracellular protein known to bind to LAT, led to abnormal movements across the IS independent of Nck.
Overall, the experiments indicated that the density of Nck and WASP proteins determine the way that LAT condensates engage actin, as switching between compositions and actin-binding modes enabled the concentrates to move at the IS. The adhesion to actin was no longer seen upon the loss of Nck and WASP/N-WASP.
“These data show that Nck and N-WASP/WASP can form a molecular clutch between LAT condensates and actin in vitro,” the researchers wrote.
“Depending on which modular molecules are used in the LAT clusters, their interaction with actin changes,” Darius Köster, PhD, one of the study’s co-authors and a professor at the Warwick Medical School, said in a press release. “It’s a bit like a clutch in your car, some molecules interact weakly with the actin, but by adding another molecule they will interact much more strongly.”
Satyajit Mayor, PhD, also an author on the study and professor at the National Centre for Biological Sciences in India, said the findings provide crucial insights into the molecular clutch formed by T-cells and the actin filaments. “This coupling in turn regulates the function of T cell receptors in aiding the immune system to recognize foreign antigens,” Mayor said.
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