Ribosomes, which build a protein (black) from an RNA strand (blue), may specialize in making particular sets of proteins.

V. ALTOUNIAN/SCIENCE

By Mitch LeslieJun. 21, 2017 , 11:00 AM

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 mRNAsand 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 readingand 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.

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There are millions of protein factories in every cell. Surprise, they're not all the same - Science Magazine

The presence of neurotransmitters in the gut is why its sometimes described as the second brain. Scientists have long known that there is cross-talk between the gut and our first brain, the central nervous system, but exactly how that communication plays out was a mystery.

Scientists finally have a better idea why certain meals send you running for the bathroom, a discovery that provides insight into the connection between your gut and brain and may point toward new therapies for intestinal disorders such as irritable bowel syndrome (IBS).

The team behind this is led by Holly Ingraham and David Julius of the University of California at San Francisco. Theyre also married, but until a few years ago, their relationship was strictly personal. Ingraham studies female metabolism, while Julius focuses on the brains response to pain. The divergent fields seemed to leave little room for collaboration until scientists in Juliuss lab made a surprising observation: Painful spider venom activates proteins in the gut.

The gut epithelium, which is the thin tissue lining that cavity, is a unique entity. Spread out all its folds and crevices and you could cover a studio apartment one that would teem with microbes, microbial signaling molecules, food byproducts and hormones. One hormone, serotonin, is a neurotransmitter that affects mood, sleep, sex drive and bowel movements. It is produced mainly by specialized enterochromaffin cells (EC), whichs make up less than 1 percent of the gut epithelium collectively, only a small end table in that studio apartment but they excrete more than 90 percent of the serotonin.

The presence of neurotransmitters in the gut is why its sometimes described as the second brain. Scientists have long known there is cross-talk between the gut and our first brain, the central nervous system, but exactly how that communication plays out has been a mystery.

Nicholas Bellono, a scientist in Julius lab, wanted to find out what neurotransmitters such as serotonin are doing in the gut, so Julius and Ingraham introduced him to James Bayrer, a gastroenterologist working in Ingrahams lab. Together, they and their collaborators in Australia co-wrote a study published Thursday in the journal Cell that demonstrates how EC cells translate chemical signals into neurological ones.

To do this, the team used mouse organoids basically, organs in a dish. The researchers isolated intestinal stem cells and used them to grow 3D mini-guts. They challenged the mini-guts with different stimuli and measured the resulting electrical responses. The method produced a very elegant model, noted Diego Bohorquez, assistant professor of medicine and neurology at Duke University, who was not involved in the research.

Gut epithelial cells are known to respond to mechanical stimulation; thats how our stomach signals its full. But the researchers found that even a light touch with certain compounds triggered an intense reaction. The EC cells were especially sensitive to adrenaline and the chemicals that give wasabi and horseradish their strong flavor. Plants in the mustard family evolved these compounds to protect themselves from insects. Our gut perceives them as a danger, causing inflammation.

To figure out the consequences of aggravating EC cells, the researchers used mice in which the cells were tagged with fluorescent molecules. They found EC cells contain receptors that recognize adrenaline, spicy food compounds and foul smells such as sweaty socks or stinky cheese. They then showed that these cells form associations with nerve fibers and produce compounds that are a hallmark of synapses the connections between nerves. When challenged with adrenaline-like compounds, the EC cells became electrically charged, and that produced a rush of serotonin that activated the nearby nerve fiber.

Bohorquez called this discovery an important step forward because it demonstrates what scientists have long suspected: Chemical stimulants electrically excite cells lining the gut, which then directly communicate with nerve cells.

There is really a gut skin cell that sits there and fires action potential like a nerve cell, said Arthur Beyder, who studies EC cells at the Mayo Clinic. Its like a Morse code. ... Theyre communicating.

The fact these cells are activated by adrenaline means the brain is in touch with the gut, as well, but we dont know why. It could be communicating with the microbiome, Beyder suggested.

These EC cells appear to specifically recognize compounds that could serve as a threat or reflect injury.

So youve got the central nervous system and the gut brain. Sometimes they talk, and sometimes they argue, and you get these gut pains, Bayrer explained. When EC cells detect an irritant, they speed up our bowels to get rid of the offender.

Ingraham noted intestinal disorders are becoming more common, especially as people age.

We dont like to talk about these issues, but constipation and diarrhea are seriously debilitating, she said.

EC cells are probably hypersensitive in people with irritable bowel syndrome. Patients often complain of discomfort or irritation, but there is not a measurable amount of inflammation. Greater understanding of normal epithelial cell activities could improve the diagnosis of IBS, Bayrer said.

Bohorquez suggested follow-up research could lead to new drugs to block EC receptors or even the use of electrical devices to minimize EC activity. An important next step will be determining if EC cells also affect the immune system, because immune cells cruise along underneath epithelial cells, Bayrer added.

Link:
Study may shed light on intestinal disorders - The News Herald