Nav: Home

Molecular 'clutch' puts infection-fighting cells into gear

July 11, 2019

  • International team including University of Warwick scientists identifies proteins that drive activation of our immune response
  • Adaptor proteins act as a 'clutch' to move clusters of proteins within cells
  • Could open opportunities to design immune cells to combat specific problems
  • Protein condensates are involved; have been found to play roles in many biological processes and diseases, including Huntington's disease, amyotrophic lateral sclerosis, and types of cancer
Two proteins that act as a 'clutch' in cells to put them in gear and drive our immune response have been identified for the first time.

A team of biochemists and cell biologists--gathered from the University of Warwick (UK), the University of Texas Southwestern (UTSW) Medical Center (USA), University of California, San Francisco (UCSF) (USA), and from the National Centre for Biological Sciences (NCBS-TIFR), Bangalore (India) -- working together at the Marine Biological Laboratory, Woods Hole in the United States thanks to funding by the Howard Hughes Medical Institute -- have uncovered a process within cells that shows how they move contents around inside them. It appears that they move in a manner similar to switching gears in a car.

The research, published in the journal eLife, could give insights into the mechanisms that activate immune cells and could eventually drive the development of new treatments.

The research focused on the composition of protein condensates - clusters of different types of proteins bound together that are found inside cells. These condensates have been found to play significant roles in many biological processes, and have also been implicated in diseases, including Huntington's disease, amyotrophic lateral sclerosis, and several types of cancer.

One system that protein condensates play an important role in is the activation of T cells, which are very important for producing antibodies and for communicating to the rest of the body that there is an infection present. T cells are constantly screening for small amounts of antigen presenting cells, which are vital for an effective adaptive immune response, so have to be easily but accurately triggered.

When a T cell binds to an antigen presenting cell, the T cell receptors are activated, and a cascade of processes are triggered. The T cell starts to rearrange its cortex and create a zone around these receptors called the immunological synapse.

A network of filaments within the cell made from actin guides a condensate carrying a protein called LAT from the cell periphery towards the centre of the cortex continuously to keep the T cell activated.

The researchers were able to demonstrate that two adaptor proteins, Nck and N-WASP/WASP, act like a 'clutch' in a car, allowing the condensate to slot into the correct gear position and speed up its progress to the centre of the cell.

The discovery sheds light on the control mechanisms for the activation of our immune response, and potentially could open opportunities to design T cells that are only active for particular problems.

Dr. Darius Köster, an Assistant Professor at the Centre for Mechanochemical Cell Biology - Warwick Medical School, explains: "Proteins condensates have distinct compositions and distinct preferential locations within cells, and they are associated with distinct biological functions, including DNA replication, RNA metabolism, signal transduction, synaptic transmission, and stress response.

"For this research, colleagues rebuilt these condensates in vitro to demonstrate that LAT can be the seed for forming these protein assemblies. We then combined this system with a rebuilt actin cortex system to get a better understanding of what happens to phase-separating protein bunches in the vicinity of an actively moving actin network.

"Depending on which modular molecules are used in the LAT clusters, their interaction with actin changes. 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.

"Using this reconstituted system allowed us to make much more minute changes to the protein condensate composition that would not be so easy to do in the live cell."

Professor Satyajit Mayor (NCBS-TIFR) commented on the unique way in which scientists from different institutes and continents came together with their respective experience and expertise to collaborate on solving a central question that is emerging in the new area of phase separating membrane-less molecular assemblies.

He comments: "This effort was made possible by a unique collaboration. An idea supported by Howard Hughes Medical Institute (HHMI), produced the 'HHMI/MBL Summer Institute', (organized primarily by the HHMI investigators Mike Rosen (UTSW), Ron Vale (UCSF) and Jim Wilhelm (UC San Diego) to study the mechanisms that control the composition and consequent function of these exciting phases in living cells. While the lead author of this study, Jon, was reconstituting the phase separating T Cell receptor signalling complex (at UTSW) along with Xiaolei Su (at UCSF), Darius brought his in vitro actomyosin membrane cortex (developed at the NCBS) to the heady collaborative atmosphere of the Marine Biological Laboratory in Woods Hole, Massachusetts. The natural consequence was to mix one system with the other. The understanding gained from this active mixture provided crucial insights into the functioning of the molecular clutch that couples the T cell signalling complex with a centripetally moving acting cytoskeleton. This coupling in turn regulates the function of T cell receptors in aiding the immune system to recognize foreign antigens."

Dr. Michael Rosen echoes this sentiment, adding: "The Summer Institute brought together scientists from across the globe to participate in a unique collaborative environment at the MBL. By living and working together for eight weeks over several summers, we were able to make scientific discoveries that would have been impossible for any of our groups individually. The work described in our eLife paper, combining extremely complex biochemistry with cutting-edge imaging and image analysis, exemplifies the spirit and accomplishments of the Summer Institute."
-end-


University of Warwick

Related Immune Response Articles:

Early immune response may improve cancer immunotherapies
Researchers report a new mechanism for detecting foreign material during early immune responses.
Researchers decode the immune response to Ebola vaccine
The vaccine rVSV-EBOV is currently used in the fight against Ebola virus.
Immune response depends on mathematics of narrow escapes
The way immune cells pick friends from foes can be described by a classic maths puzzle known as the 'narrow escape problem'.
Signature of an ineffective immune response to cancer revealed
Our immune system is programmed to destroy cancer cells. Sometimes it has trouble slowing disease progression because it doesn't act quickly or strongly enough.
Putting the break on our immune system's response
Researchers have discovered how a tiny molecule known as miR-132 acts as a 'handbrake' on our immune system -- helping us fight infection.
Having stressed out ancestors improves immune response to stress
Having ancestors who were frequently exposed to stressors can improve one's own immune response to stressors, according to Penn State researchers.
Researchers discovered new immune response regulators
The research groups of Academy Professor Riitta Lahesmaa and Research Director Laura Elo from Turku Centre for Biotechnology have discovered new proteins that regulate T cells in the human immune system.
Blueprint for plant immune response found
Washington State University researchers have discovered the way plants respond to disease-causing organisms, and how they protect themselves, leading the way to potential breakthroughs in breeding resistance to diseases or pests.
Immune response mechanism described for fate determination of T cells
In a paper published in the journal Science, University of Alabama at Birmingham researchers and colleagues at four other United States institutions have detailed a mechanism that sets the stage for the fate decision that gives rise to two major subsets of effector cells: T follicular helper cells and non-T follicular helper cells, known as Tfh and non-Tfh cells.
Retinoic acid may improve immune response against melanoma
University of Colorado Cancer Center clinical trial results describe a promising strategy to remove one of melanoma's most powerful defenses: By adding retinoic acid to standard-of-care treatment, researchers were able to turn off myeloid-derived suppressor cells (MDSCs) that turn off the immune system, leading to more immune system activity directed at melanoma.
More Immune Response News and Immune Response Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab