Key epigenetic phosphorylation pathway identified that protects cells against death by stress.


When it comes to protecting cells from death brought on by the calamities of environmental stress, the human body is particularly ingenious. From cellular components that suck up misfolded proteins to a vigilant immune system, the ways the body protects it’s cells are many.  Scientists from The Scripps Research Institute (TSRI) and Johns Hopkins University have now uncovered the workings of another cell-protection device, one that may play a major role in a number of age-related diseases, including diabetes and Parkinson’s, Alzheimer’s and Huntington’s diseases.  The opensource study is published in the journal Cell Reports.

The current study focuses on a new pathway through which Rheb, a regulator that many believe is active in the brain’s ability to change in response to learning, actually plays two roles, rather than one, stimulating and inhibiting protein synthesis.

The interplay between the two roles may be the key that enables cells to alter protein synthesis and protect the cell in response to varying environmental stresses.

The team explain that Rheb acts like the gas pedal in a car.  It can either increase translation or decrease it. And because translation is a fundamental process that is affected in a lot of diseases, the researchers now think that Rheb may act like a switch in some disease states, helping to turn them off and on.

Rheb is known to bind and activate mTOR, a developmentally important gene that integrates signals from multiple pathways and regulates critical cell functions such as protein synthesis. Besides its role as an activator of mTOR, which plays a major role in conditions from diabetes to neurodegenerative disease, the mTOR-independent role of Rheb is less known.

The current study defines crucial mTOR-independent effects of Rheb. Results showed that, when stressed, Rheb instead inhibits protein synthesis by amplifying the phosphorylation (adding a phosphate group to a protein to alter its function) of another protein known eIF2α. As a result, cell resources can be conserved rather than squandered when the environment is challenging.

The team explain that even though they don’t fully understand the role of the Rheb-mTOR pathway, they have uncovered a new fundamental process of Rheb that is independent of mTOR and very intriguing.  Rheb can inhibit protein synthesis, and researchers know that protein misfolding via environmental stress factors is present in a lot of diseases.

The team also note that, intriguingly, an earlier study had suggested the Rheb pathway had been implicated in Alzheimer’s disease.  The team now plan to look at Rheb’s role in other neurodegenerative diseases.

Source:  The Scripps Research Institute (TSRI) 

 

Rheb, a ubiquitous small GTPase, is well known to bind and activate mTOR, which augments protein synthesis. Inhibition of protein synthesis is also physiologically regulated. Thus, with cell stress, the unfolded protein response system leads to phosphorylation of the initiation factor eIF2α and arrest of protein synthesis. We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK). Interplay between the stimulatory and inhibitory roles of Rheb may enable cells to modulate protein synthesis in response to varying environmental stresses.  Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade.  Subramaniam et al 2015.

Rheb, a ubiquitous small GTPase, is well known to bind and activate mTOR, which augments protein synthesis. Inhibition of protein synthesis is also physiologically regulated. Thus, with cell stress, the unfolded protein response system leads to phosphorylation of the initiation factor eIF2α and arrest of protein synthesis. We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK). Interplay between the stimulatory and inhibitory roles of Rheb may enable cells to modulate protein synthesis in response to varying environmental stresses. Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade. Subramaniam et al 2015.

 

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