The Case of the Unknown Protein

Architecture of MESH1
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The Case of the Unknown Protein

The surprising function of the human version of a bacterial protein solves a long-time mystery

By Alissa Kocer

After a trip to the grocery store, you may find yourself with seemingly unlimited options on what to eat, but ten days later, you might be looking at bare shelves and trying to decide between ramen noodles or the slightly grayish looking leftovers from who knows when. Some animals, too, tend to feast when food abounds to help prepare for those months of scarce resources.  

“All living organism, from bacteria to human cancer cells, have to find a way to deal with stresses, including nutrient depletion,” said Ashley Chi, associate professor in molecular genetics and microbiology at Duke University.

In bacteria, the primary pathway for stress is called the stringent response. This well-known response allows bacteria to temporarily stop processes that require a lot of energy consumption in order to survive harsh times. In other words, like a bear in the winter, they hibernate. Bacteria get the cue to slow down when the signal molecule alarmone accumulates. Two enzymes, RelA synthetase and SpoT hydrolase, responsible for synthesizing and degrading the bacterial alarmone, collectively regulate the bacterial stringent response. 

About a decade ago, the human counterpart of SpoT, called MESH1 (Metazoan SpoT Homolog), was discovered, but researchers were unsure of its function. Some research suggested that it could mediate some stress-related function because it can process bacterial alarmone, but alarmone has never been detected in human cells before, so that notion was controversial at best. 

Chi, in collaboration with Pei Zhou, professor of biochemistry, along with their trainees Chien-Kuang Ding, Alice Sun and Josh Rose, cracked the case. In research published in the March issue of Nature Metabolism, they describe their discovery of a similar response in human cells with the help of MESH1.

When MESH1 is activated under stress conditions, the central metabolite, NADPH, is depleted and ferroptosis, a type of programmed cell death, occurs. If MESH1 is silenced, the human version of the stringent response is set into motion: NADPH levels are maintained and cells do not die from ferroptosis.

They also uncovered the structure of the MESH1-NADPH complex, which is phenotypically similar but mechanistically divergent to the bacterial structure so it can recognize NADPH. It’s like going from a gas powered car to an electric: They don’t look all that different. They both have doors, pedals, seats, steering wheel in all the same places, but the way the engines work is totally different. 

“This system in our bodies is left over from billions of years from bacteria and we never knew we had it,” Chi said.

The next steps will be to explore the biomedical implications of this discovery, especially as it pertains to metabolic diseases, like cancer. 

CITATION: "MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis,” Chien-Kuang Cornelia Ding, Joshua Rose, Tianai Sun, Jianli Wu, Po-Han Chen,Chao-Chieh Lin, Wen-Hsuan Yang, Kai-Yuan Chen, Hana Lee, Emily Xu, Sarah Tian, Jadesola Akinwuntan, Jinshi Zhao, Ziqiang Guan, Pei Zhou and Jen-Tsan Chi. Nature Metabolism, March 9, 2020. DOI: 10.1038/s42255-020-0181-1
https://www.nature.com/articles/s42255-020-0181-1.

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