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How Do Living Cells Survive When Skipping A Paycheck?

First, they cut expenses and then recycle hand-me-downs, but how do they know ahead of time that the money is running out? Recent research on baker’s yeast uncovered a new way cells slow their growth down when nutrients are running low. This information from an improbable source provides new insight into a family of uncharacterized human genes, some of which cause severe neurological disorders, epilepsy, and possibly autism when mutated.

Bacterial, fungal, and human cells have a sense of their environment and can retool their metabolism for leaner times when they detect a decline in the food source, thereby avoiding death by starvation. But how do cells detect food? It is not currently known if cells can detect all individual types of nutrients, but it is clear that cells are particularly well equipped to sense and respond to the amino acid leucine and to the sugar glucose.

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Why leucine? Perhaps because leucine is one of the most abundant amino acids in the body’s proteins and, therefore, cells may have evolved to use leucine as a type of sentinel for food availability. Presumably, leucine binds to one or more sensors inside cells, sending a signal to a command center that receives messages about the cell’s nutrient status and drives many different cellular behaviors accordingly. This major command center is a protein complex in cells known as the target of rapamycin complex 1, TORC1. Although the details are only partially delineated, the leucine that cells take up from the environment or retrieve from internal recycling stores can activate TORC1 within minutes to trigger a cascade of events, telling cells to get busy because nutrients are available.

But how does TORC1 know to shut down when leucine levels fall? The best-known mechanism is by putting the engine that drives TORC1 (human RAG GTPases, GTR GTPases in yeast) into reverse mode. However, an entirely new way to tell TORC1 that leucine is running low was recently discovered in yeast, this strategy requires the protein Whi2. Although the details are not yet known, Whi2 together with its partner phosphatases Psr1-Psr2 turns off TORC1 to prevent uncontrolled growth when there is not enough food to sustain both growth and survival. Surprisingly, Whi2 is only important to communicate low leucine conditions and is not needed to inhibit TORC1 or slow cell growth in low glucose or any other amino acid, just low leucine.

Uninhibited growth may sound like a good idea for yeast, but cells without Whi2 are like big-spenders with no reserves for a rainy day. Without Whi2 (wee-2), cells are smaller and sicker, apparently because they don’t know how to stop dividing when there is insufficient food. As a result, they crash when stressed, apparently because they can’t activate their recycling program or turn on other stress responses.

These discoveries led to the identification of Whi2-like human counterparts. Like yeast Whi2, the tumor suppressor human KCTD11 is also required to inhibit TORC1 in low amino acid conditions. Mutations in another Whi2-like human protein KCTD7 cause a severe neurological disorder in children such that their brains collect undegraded junk at young ages, similar to the normal aged brain. Like yeast without Whi2, cultured cells from patients without KCTD7 have a defective recycling program known as autophagy.

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These findings may help understand other diseases caused by mutations in other Whi2-related human proteins like KCTD13, which is associated with autism and schizophrenia in a subset of patients, and KCTD17, thought to cause movement disorders in adults. This discovery of how Whi2 controls cell responses to low nutrients is a great example of how unexpected discoveries gleaned from pure basic science research can yield insights into newly-identified diseases of unknown etiology.

These findings are described in the article entitled Whi2 is a conserved negative regulator of TORC1 in response to low amino acids, published in the journal PLoS Genetics, the article Whi2 signals low leucine availability to halt yeast growth and cell death., published in FEMS Yeast, and the article entitled KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect, published in the journal Annals of Neurology(on the cover of November issue). This work was conducted by the laboratories of J. Marie Hardwick at Johns Hopkins University School of Public Health and Xinchen Teng at Soochow University, China.

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