Sept. 16, 2014
Living cells are like miniature
factories, responsible for the production of more than 25,000 different
proteins with very specific 3-D shapes. And just as an overwhelmed assembly
line can begin making mistakes, a stressed cell can end up producing misshapen
proteins that are unfolded or misfolded.
A color-enhanced electron micrograph shows
the nucleus of a cell (blue) adjacent to the rough endoplasmic reticulum
(green), where proteins are manufactured from mRNA templates produced by the
nucleus.
Credit: University of Edinburgh, via the
Wellcome Trust
Now Duke University researchers
in North Carolina and Singapore have shown that the cell recognizes the buildup
of these misfolded proteins and responds by reshuffling its workload, much like
a stressed out employee might temporarily move papers from an overflowing inbox
into a junk drawer.
The study, which appears in
Cell, could lend insight into diseases that result from misfolded proteins
piling up, such as Alzheimer's disease, ALS, Huntington's disease, Parkinson's disease, and type 2 diabetes.
"We have identified an
entirely new mechanism for how the cell responds to stress," said
Christopher V. Nicchitta, Ph.D., a professor of cell biology at Duke University
School of Medicine. "Essentially, the cell remodels the organization of
its protein production machinery in order to compartmentalize the tasks at
hand."
The general architecture and
workflow of these cellular factories has been understood for decades. First,
DNA's master blueprint, which is locked tightly in the nucleus of each cell, is
transcribed into messenger RNA or mRNA. Then this working copy travels to the
ribosomes standing on the surface of a larger accordion-shaped structure called
the endoplasmic reticulum (ER). The ribosomes on the ER are tiny assembly lines
that translate the mRNAs into proteins.
When a cell gets stressed,
either by overheating or starvation, its proteins no longer fold properly.
These unfolded proteins can set off an alarm - called the unfolded protein
response or UPR - to slow down the assembly line and clean up the improperly folded
products. Nicchitta wondered if the stress response might also employ other
tactics to deal with the problem.
In this study, Nicchitta and his
colleagues treated tissue culture cells with a stress-inducing agent called
thapsigargin. They then separated the cells into two groups - those containing
mRNAs associated with ribosomes on the endoplasmic reticulum, and those
containing mRNAs associated with free-floating ribosomes in the neighboring
fluid-filled space known as the cytosol.
The researchers found that when
the cells were stressed, they quickly moved mRNAs from the endoplasmic
reticulum to the cytosol. Once the stress was resolved, the mRNAs went back to
their spots on the production floor of the endoplasmic reticulum.
"You can slow down protein
production, but sometimes slowing down the workflow is not enough,"
Nicchitta said. "You can activate genes to help chew up the misfolded
proteins, but sometimes they are accumulating too quickly. Here we have
discovered a mechanism that does one better - it effectively puts everything on
hold. Once things get back to normal, the mRNAs are released from the holding
pattern."
Interestingly, the researchers
found that shuttling ribosomes between the ER and the cytoplasm during stress
only affected the subset of mRNAs that would give rise to secreted proteins
like hormones or membrane proteins like growth factor receptors - the types of
proteins that set off the stress response if they're misfolded. They aren't
sure yet what this means.
Nicchitta is currently searching for the
factors that ultimately determine which mechanisms cells employ during the
stress response. He has already pinpointed one promising candidate, and is
looking to see how cells respond to stress when that factor is manipulated.
