Environmental stress can cause cells to react in several ways. The most deleterious of these reactions is the activation of molecular pathways that lead to cell death. Many organisms have evolved countermeasures that either prevent the stress pathways from activating or block the signaling cascade to achieve its final goal of cell degradation.
Now, scientists from The Scripps Research Institute (TSRI) Florida campus have discovered another pathway that serves as cell protection and may play a critical role in age-related neurological disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. The research was published today in Cell Reports in an article entitled “Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade”.
The study focuses on a GTP-binding protein known as Ras homolog enriched in bran (Rheb), which the researchers reveal plays two opposing roles in protein synthesis, in one portion of the pathway it stimulates and in another it inhibits. The investigators believe that it is the interplay between the dichotomous states of Rheb that enables cells to alter protein synthesis in response to environmental stressors, ultimately leading to cell protection.
“We found Rheb acts like the gas pedal in a car,” stated Srinivasa Subramaniam, Ph.D., assistant professor of neuroscience at TSRI, Florida and senior author on the current study. “It can either increase translation or decrease it. And because translation is a fundamental process that is affected in a lot of diseases, we now think that Rheb may act like a switch in some disease states—helping to turn them off and on.”
One of Rheb’s targets is the serine/threonine protein kinase mTOR, which has been well characterized as an important regulator of cell proliferation, growth, motility, and protein synthesis. In this current study Dr. Subramaniam and his team wanted to look at the mTOR-independent role of Rheb, which is much less understood. Interestingly, the team found that in times of stress, Rheb will inhibit protein synthesis through the increased phosphorylation of the protein eIF2α, which is an integral cog in the cellular degradation and death pathways, autophagy, and apoptosis.
“We don’t really understand the full role of the Rheb-mTOR pathway, but we have uncovered a new fundamental process of Rheb that is independent of mTOR and very intriguing,” said Neelam Shahani, Ph.D., senior research associate in Dr. Subramaniam’s lab and co-first author of the study. “Rheb can inhibit protein synthesis, and we know that protein misfolding via environmental stress factors is present in a lot of diseases.”
The researchers are currently looking at what the future holds of Rheb. Since earlier studies have indicated a possible role for Rheb in Alzheimer’s disease, Dr. Subramaniam said that “We also want to look at Rheb’s role in other neurodegenerative diseases.”