The plant that built your computer isn't churning out cars and toys as well. But many researchers think cells' crucial protein factories, organelles known as ribosomes, are interchangeable, each one able to make any of the body's proteins. Now, a provocative study suggests that some ribosomes, like modern factories, specialize to manufacture only certain products. Such tailored ribosomes could provide a cell with another way to control which proteins it generates. They could also help explain the puzzling symptoms of certain diseases, which might arise when particular ribosomes are defective.
Biologists have long debated whether ribosomes specialize, and some remain unconvinced by the new work. But other researchers say they are sold on the finding, which relied on sophisticated analytical techniques. "This is really an important step in redefining how we think about this central player in molecular biology," says Jonathan Dinman, a molecular biologist at the University of Maryland in College Park.
A mammalian cell may harbor as many as 10 million ribosomes, and it can devote up to 60% of its energy to constructing them from RNA and 80 different types of proteins. Although ribosomes are costly, they are essential for translating the genetic code, carried in messenger RNA (mRNA) molecules, into all the proteins the cell needs. "Life evolved around the ribosome," Dinman says.
The standard view has been that a ribosome doesn't play favorites with mRNAs—and therefore can synthesize every protein variety. But for decades, some researchers have reported hints of customized ribosomes. For example, molecular and developmental biologist Maria Barna of Stanford University in Palo Alto, California, and colleagues reported in 2011 that mice with too little of one ribosome protein have short tails, sprout extra ribs, and display other anatomical defects. That pattern of abnormalities suggested that the protein shortage had crippled ribosomes specialized for manufacturing proteins key to embryonic development.
Definitive evidence for such differences has been elusive, however. "It's been a really hard field to make progress in," says structural and systems biologist Jamie Cate of the University of California (UC), Berkeley. For one thing, he says, measuring the concentrations of proteins in naturally occurring ribosomes has been difficult.
In their latest study, published online last week in Molecular Cell, Barna and her team determined the abundances of various ribosome proteins with a method known as selected reaction monitoring, which depends on a type of mass spectrometry, a technique for sorting molecules by their weight. When the researchers analyzed 15 ribosomal proteins in mouse embryonic stem cells, they found that nine of the proteins were equally common in all ribosomes. However, four were absent from 30% to 40% of the organelles, suggesting that those ribosomes were distinctive. Among 76 ribosome proteins the scientists measured with another mass spectrometry-based method, seven varied enough to indicate ribosome specialization.
Barna and colleagues then asked whether they could identify the proteins that the seemingly distinctive ribosomes made. A technique called ribosome profiling enabled them to pinpoint which mRNAs the organelles were reading—and thus determine their end products. The specialized ribosomes often concentrated on proteins that worked together to perform particular tasks. One type of ribosome built several proteins that control growth, for example. A second type churned out all the proteins that allow cells to use vitamin B12, an essential molecule for metabolism. That each ribosome focused on proteins crucial for a certain function took the team by surprise, Barna says. "I don't think any of us would have expected this."
Ribosome specialization could explain the symptoms of several rare diseases, known as ribosomopathies, in which the organelles are defective. In Diamond-Blackfan anemia, for instance, the bone marrow that generates new blood cells is faulty, but patients also often have birth defects such as a small head and misshapen or missing thumbs. These seemingly unconnected abnormalities might have a single cause, the researchers suggest, if the cells that spawn these different parts of the body during embryonic development carry the same specialized ribosomes.
Normal cells might be able to dial protein production up or down by adjusting the numbers of these specialized factories, providing "a new layer of control of gene expression," Barna says. Why cells need another mechanism for controlling gene activity isn't clear, says Cate, but it could help keep cells stable if their environment changes.
He and Dinman say the use of "state-of-the-art tools" makes the results from Barna's team compelling. However, molecular biologist Harry Noller of UC Santa Cruz doubts that cells would evolve to reshuffle the array of proteins in the organelles. "The ribosome is very expensive to synthesize for the cell," he says. If cells are going to tailor their ribosomes, "the cheaper way to do it" would entail modifying a universal ribosome structure rather than building custom ones.