Assistant Professor, Technion
Recommended by Susan Lindquist, Massachusetts Institute of Technology
NEW YORK (GenomeWeb) – As a postdoc, Reut Shalgi was using high-throughput genomic approaches like RNA-seq and others to characterize the gene and protein expression profiles of heat-shock stressed cells, when she instead found that ribosomes would pause in their translational duties. Using a ribosome foot-printing method, she and her colleagues found that ribosomes stopped translating right in the middle of their protein message, usually when the nascent proteins were just beginning to peek out the end of the ribosome tunnel.
"Almost all mRNAs in the cell showed this. ... They are all pausing and waiting," Shalgi told GenomeWeb. "This was very striking."
This, she added, appeared to be a new level of translation regulation at the elongation step.
Because Shalgi and her colleagues were looking at a heat shock model and because they noted a correlation between the hydrophobicity of the growing peptide chain and how long the ribosome paused, they suspected that chaperones like Hsp70 might be involved. Indeed, they found when chaperones were less frequently associated with the ribosomes, pausing was more likely to occur. This indicated, Shalgi added, that there is crosstalk between the protein-synthesis and protein-folding processes.
"This is what I am interested in now the most: how they talk to each other and under what circumstances they talk to each other, how is the flow of information transferred, and what are the factors that are involved?" she said. "Is there information in the nascent peptide itself that can lead to translational control in the absence or presence of a chaperone that is sitting on the ribosome?"
Additionally, she is interested in how this pausing may be relevant to diseases, particularly neurodegenerative diseases in which misfolded proteins play a role.
In her new lab at the Technion, Shalgi is setting up to study how widely ribosomal pausing occurs, the dynamics of the chaperone-ribosome association, and what factors affect that association.
However, her lab is quite new, and, Shalgi said, just setting out can be a challenge as she goes about filling her lab with the tools and technologies she needs — in her case, some tools that are new to Israel — as well as finding the right people to work with.
"You need the right equipment and the right people to come together and really help you carry out this vision that you have," she said.
Paper of note
Shalgi was the first author on the 2013 Molecular Cell paper showing that elongation pausing occurs in human and mouse cells. In it, she and her colleagues reported using a ribosome footprinting approach to show that two hours of heat stress could lead to a global pausing of elongation around codon 65 of most mRNAs. They further implicated Hsp70 by showing that its overexpression protects cells from pausing, while inhibiting it led to elongation pausing, even in the absence of heat shock stress.
"Some people were skeptical at first because it's not trivial that chaperones will be involved in translational control; it basically was unheard of before that, and it turned out to be true, so I feel really very, very proud of this work," she said.
New sequencing and other technologies are churning out reams of data, and Shalgi noted that this means that researchers have to contend with how to tease biological insights out of that data.
"That's still, I think, in progress, but I think we are getting there, we are making progress in that aspect," she said. And the next step, she added, is to then relate these new findings to disease.
And the Nobel goes to…
Shalgi said that her interest is mostly on the basic science aspect of biology and medicine, and so if she were to receive the Nobel Prize, she'd like it to be for uncovering how different cellular systems are interconnected and can communicate. For instance, she said, it could be for "discovering how chaperones are able to communicate this status of proteins in the cell to all the other systems in the cell, including ribosomes."
This is the thirteenth in a series of Young Investigator Profiles for 2015 that will appear on GenomeWeb over the next few months.