Researchers at the University of Michigan have revealed that cells use a previously unknown feat of molecular craftsmanship to help protect their larger host organisms.
The building blocks required for this work are found across the tree of life, meaning this finding could help better understand and support plant resilience and human immune response, the researchers said.
“This is going to be interesting to a broad biological field,” said Libo Shan, a senior leader of the project and a professor in the U-M Department of Molecular, Cellular, and Developmental Biology, or MCDB. “We feel that this will raise some very exciting follow up work in medicine and agriculture.”
Co-led by MCDB professor Ping He, the research, supported by federal funding from the National Institutes of Health, was published in the journal Nature.
Put a ring on it
One of the ways individual cells can protect their host organism from disease is by sacrificing themselves to prevent the spread of pathogens. This programmed cell death is an effective but delicate operation, He said. It can stop a disease from advancing if enough compromised cells are eliminated. But an overzealous response can claim healthy cells, which would also harm the larger host organism.
“Cell death may sound like a bad thing, but in plants and mammals, it’s a marker of resistance,” He said. “We need to have this defense, but it is also important to have this defense in a limited area and that’s what this study is talking about.”
Over the past several decades, researchers have identified the genes and proteins in plants that initiate the cellular self-destruct sequence. During that time, they also found shared elements of this “resistome” at work in mammalian cells (thanks, in part, due to earlier research at Michigan Medicine).
Still, scientists are working hard to map out the processes’ complete molecular choreography to understand how cells coordinate cell death without it becoming overkill.
Recent studies in immunology revealed a key new move, that proteins involved in the process come together to form channels that can shuttle calcium ions. By themselves, however, these channels weren’t sufficient to initiate cell death. Now, He, Shan and their team have revealed an important next step.
“For the first time, we’ve shown how the channels organize into a beautiful ring structure on the cell membrane,” Shan said.
The ring, which resembles a wreath or a necklace, Shan said, is a combination of proteins that bind to a cell membrane and six channels that orient themselves to run through the membrane. The team made this discovery working with Arabidopsis and Nicotiana bethamaian, popular plant model systems, and a high resolution total internal reflection fluorescence microscope purchased with NIH funding.The finding invites new questions about what exactly the rings do and how they do it. The team’s current hypothesis is that the rings enable communication with nearby cells, sending inflammation signals that can help initiate cell death in a targeted way. Shan, He and their team are now working with the U-M Life Science Institute and its Cryo-Electron Microscopy Lab to examine the rings in greater detail.
“The next thing that we’re doing is looking at what kinds of things could be leaking out through this structure, and also what supports the ring structure formation,” Shan said. “We haven’t answered all the questions, but we have advanced the field.”
While these next steps are already yielding interesting results, the researchers remained excited about the new study’s potential to help others who are exploring fundamental biological questions and potential applications. For example, the discovery could open up new avenues for scientists working to make plants more resilient and to treat conditions where cell death runs amok in humans.”We know there are a lot of unknowns with this ring hanging on the ceiling of cells, but we know it is absolutely required to have the perfect amount of cell death, to have the perfect immune response,” Shan said. “We truly believe this work will lay the foundation to launch a wave of exciting research for continued discovery.”
