Make way for hemoglobin

August 18, 2017
Credit: CC0 Public Domain

Every cell in the body, whether skin or muscle or brain, starts out as a generic cell that acquires its unique characteristics after undergoing a process of specialization. Nowhere is this process more dramatic than it is in red blood cells.

In order to make as much room as possible for the oxygen-carrying protein hemoglobin, pretty much everything else inside these precursor red blood cells—nucleus, mitochondria, ribosomes and more—gets purged. Jam-packing red blood cells with hemoglobin is essential. Doing so ensures that all the body's tissues and organs are well nourished with oxygen to carry on their normal functions.

But how does this cell remodeling take place to begin with?

For more than 20 years, Daniel Finley, professor of cell biology at Harvard Medical School, has been on a quest to unravel the process behind this profound cellular transformation.

Now, thanks to advances in technology and a fortuitous meeting with researchers in a lab at Boston Children's Hospital, Finley and his collaborators have identified the mechanism behind specialization and revealed that it is controlled by an enzyme he first studied in 1995.

Their findings, published Aug. 4 in the journal Science, could spark the development of new treatments for blood disorders and cancers.

"The creation of highly specialized cells is very important for processes such as oxygen delivery to tissues, our ability to see and reproduce, and to make skin," Finley said. "Understanding exactly how this happens gives us better insight into some of the most fundamental properties of living things."

During cell specialization, unwanted parts of a generic, immature cell are removed by the proteasome, protein-gobbling strings of molecules, or the cells' "trash compactors," says study first author Anthony Tuan Nguyen, an HMS MD-PhD student.

The researchers set out to find the mechanism that controls which parts get destroyed and which parts are spared before the precursor red blood cell becomes a full-fledged one.

Finley had a hunch that the process was controlled by an enzyme called UBE2O, which he and colleagues identified in the 1990s. The enzyme marks cell parts for destruction by tagging them with a small protein called ubiquitin. This tagging allows the proteasome to recognize cells destined for destruction. The vast machinery, known as the ubiquitin-proteasome system (UPS), is switched on constantly throughout the body to remove unnecessary proteins and keep cells free of clutter.

Previously, UPS had not been linked to the specialization of red blood cells. However, in his early research on UBE2O, Finley had noticed large amounts of the enzyme present in immature red blood cells. That was a powerful clue. The combination of UBE2O's pronounced presence and its known function as cellular debris-remover made it a promising candidate for the role of a key regulator of cell specialization. Yet, back when he first came to this realization, Finley had neither the technology nor the funding to analyze red blood cell development at the necessary molecular detail.

"It was the fish that got away," he said.

Twenty years later, the pieces Finley needed to reopen his abandoned investigation fell into place when he met Mark Fleming, HMS professor of pathology at Boston Children's Hospital. While studying blood cells, Fleming had identified a mutant mouse that lacked the UBE2O enzyme. Knowing that Finley was interested in the enzyme and its possible role in cell specialization, Fleming contacted him.

The researchers observed that mice without the enzyme were anemic, a marker of red blood cell deficiency. The observation supported the notion that UBE2O may play a role in red blood cell development.

Using a series of tests that relied on large-scale protein analyses not available in earlier decades, the researchers confirmed the enzyme's role. Their results revealed that immature red blood cells lacking UBE2O retained hundreds of proteins and failed to become specialized.

The researchers also demonstrated that when isolated from immature red blood cells and tested in other cell types, UBE2O still marked the right proteins for destruction, suggesting that the enzyme is the primary regulator of red blood cell specialization.

The researchers have yet to determine whether the mechanism they found in red blood cells controls specialization of other cells as well. Finley says it probably does.

"I think our work calls attention to the complicated processes behind the development of specialized cells, which is seen throughout nature," Finley said.

Because the plays an important role in the development of red blood , the researchers say they hope their work could lead to therapies for certain and blood cancers. The present study revealed that, in mice, UBE2O deficiency powerfully suppressed the symptoms of a disorder known as beta thalassemia. This aspect of the research is particularly tantalizing to Nguyen, who has a gene mutation linked to the condition.

"It was really exciting to identify and study a possible treatment for this genetic disease," Nguyen said. "Especially since it may affect me personally."

Explore further: Blood study insight could improve stem cell therapy success

More information: Anthony T. Nguyen et al, UBE2O remodels the proteome during terminal erythroid differentiation, Science (2017). DOI: 10.1126/science.aan0218

Related Stories

Blood study insight could improve stem cell therapy success

May 12, 2017
Researchers have pinpointed a key enzyme that is vital for the production of fresh blood cells in the body. The enzyme is essential for the survival of specialised stem cells that give rise to new blood cells, the study found. ...

New role discovered for a well-known gene in the survival of white blood cells

May 31, 2017
Researchers have clarified the role of a gene critical for the development of a type of white blood cells, known as B cells, which produce antibodies and serve as a "memory" for the immune system. This finding may open up ...

New types of blood cells discovered

April 21, 2017
Scientists have identified new classes of cells in the human immune system.

DNA-altering enzyme is essential for blood cell development

June 10, 2013
The expression of specific genes is partially dictated by the way the DNA is packed into chromatin, a tightly packed combination of DNA and proteins known as histones. HDAC3 is a chromatin-modifying enzyme that regulates ...

Scientists successfully create blood from skin cells

November 21, 2016
Researchers in Singapore have artificially generated new mouse blood and immune cells from skin cells. This is a significant first step towards the eventual goal: the engineering of new human blood cells from skin cells or ...

Recommended for you

Thousands of new microbial communities identified in human body

September 20, 2017
A new study of the human microbiome—the trillions of microbial organisms that live on and within our bodies—has analyzed thousands of new measurements of microbial communities from the gut, skin, mouth, and vaginal microbiome, ...

Study finds immune system is critical to regeneration

September 20, 2017
The answer to regenerative medicine's most compelling question—why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot—may lie with the body's innate immune system, ...

Immune cells produce wound healing factor, could lead to new IBD treatment

September 20, 2017
Specific immune cells have the ability to produce a healing factor that can promote wound repair in the intestine, a finding that could lead to new, potential therapeutic treatments for inflammatory bowel disease (IBD), according ...

As men's weight rises, sperm health may fall

September 20, 2017
(HealthDay)—A widening waistline may make for shrinking numbers of sperm, new research suggests.

New model may help science overcome the brain's fortress-like barrier

September 19, 2017
Scientists have helped provide a way to better understand how to enable drugs to enter the brain and how cancer cells make it past the blood brain barrier.

Cell-based therapy success could be boosted by new antioxidant

September 19, 2017
Cell therapies being developed to treat a range of conditions could be improved by a chemical compound that aids their survival, research suggests.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.