Enzyme found to control formation of collagen carriers and inhibit collagen secretion

June 11, 2018, Tokyo Institute of Technology
Electron microscopy imaging reveals the presence of many interconnected vesicles, which appear to behave like collagen carriers (indicated by arrows). Credit: Biochemical and Biophysical Research Communications

Researchers at Tokyo Institute of Technology (Tokyo Tech) have identified an enzyme that controls how much collagen cells secrete. As collagen imbalance is linked to a range of human diseases, the study provides clues to new therapeutic strategies. Moreover, the findings could facilitate efficient production of collagen for the food, cosmetic and pharmaceutical industries.

All cells make and release proteins. The proteins are packaged as "cargo" in tiny, bubble-like vesicles before being transported outside the cell. This process, known as , is vital to healthy growth and development.

Although many studies have shown how these vesicles, called COPII carriers, handle relatively small-sized cargo, few have focused on the workings of unusually large carriers known to package very large proteins, such as collagen.

Now, a study by researchers including Masayuki Komada, Toshiaki Fukushima and graduate student Kohei Kawaguchi at Tokyo Institute of Technology has identified USP8 as a key enzyme involved in controlling the formation of large collagen carriers. They have reported their findings in the journal Biochemical and Biophysical Research Communications.

The team showed that "switching on" USP8 inhibited the formation of large carriers, and thus reduced collagen secretion. Conversely, switching USP8 off promoted collagen transport, which led to increased collagen secretion. (See Figures 1-3.)

Immunostaining experiments revealed a high concentration of collagen (green signals) in the Golgi region prior to secretion. Credit: Biochemical and Biophysical Research Communications

The findings have big implications for medicine and biotechnology. Excessive collagen secretion in the human body is known to cause organ fibrosis, while too little collagen secretion is associated with bone diseases including cranio-lenticulo-sutural dysplasia (CLSD) and Cole-Carpenter syndrome. New treatments for these diseases could be developed through further understanding of USP8's exact mode of action. Such knowledge could also provide new ways of scaling up commercial production of .

The researchers have demonstrated that the enzyme works by deubiquitinating a called Sec31A, a component of the COPII vesicle coat required for protein export.

One particular group of proteins called the USP8-STAM1 complex appears to be responsible for deubiquitinating Sec31A, as illustrated in Figure 3.

The study builds on many years of research that have illuminated the versatility of USP8.

Enzyme found to control formation of collagen carriers and inhibit collagen secretion
Relatively small-sized proteins (on the left) and large collagens (on the right) are encapsulated by COPII carriers of suitable sizes prior to secretion. The USP8-STAM1 complex inhibits the formation of large collagen carriers. Credit: Biochemical and Biophysical Research Communications

"We had previously reported that USP8 regulates pituitary hormone secretion," says Fukushima, referring to a paper published in Nature Genetics in 2015. "In the process of that study, we accidentally found that the USP8-STAM1 complex binds to Sec31."

It was this "accidental" finding, combined with promising results from other groups in the US, that led the team to examine the role of USP8 in the formation of COPII carriers.

In research tracing back more than a decade, Komada and others have clarified the conventional role of USP8 in the regulation of endocytosis5. "It's very interesting that the same USP8-STAM1 complex has now been shown to play an important role both in the regulation of endocytosis and in secretion," Fukushima says.

The present study therefore reveals a "new face" of the USP8 enzyme, and Fukushima hints that there may be more surprises to come. USP8 belongs to a family of around 90 known deubiquitinating enzymes, which continue to be a hot topic in cellular biology.

Explore further: Mutations drive unrestrained secretion

More information: Kohei Kawaguchi et al, Ubiquitin-specific protease 8 deubiquitinates Sec31A and decreases large COPII carriers and collagen IV secretion, Biochemical and Biophysical Research Communications (2018). DOI: 10.1016/j.bbrc.2018.03.202

Related Stories

Mutations drive unrestrained secretion

December 10, 2014

Benign tumors in the pituitary gland lead to uncontrolled secretion of the stress hormone cortisol by the cells of the adrenal cortex. An international research effort has now characterized a new mechanism that triggers the ...

Decrypting a collagen's role in schizophrenia

March 14, 2016

A small peptide generated from a collagen protein may protect the brain from schizophrenia by promoting the formation of neuronal synapses, according to a paper published in The Journal of Cell Biology. The study, "Collagen-Derived ...

More realistic and accurate organs-on-chips

March 7, 2018

In a step toward better diagnosis and treatment of digestive conditions, such as inflammatory bowel disease, scientists report in ACS Biomaterials & Engineering that they have developed a first-of-its-kind collagen-based ...

New cellular insights in bone development

April 6, 2018

Most of us don't think about our teeth and bones until one aches or breaks. A team of engineers at Washington University in St. Louis looked deep within collagen fibers to see how the body forms new bone and teeth, seeking ...

Recommended for you

Research team uncovers lost images from the 19th century

June 22, 2018

Art curators will be able to recover images on daguerreotypes, the earliest form of photography that used silver plates, after a team of scientists led by Western University learned how to use light to see through degradation ...

Detecting metabolites at close range

June 22, 2018

A novel concept for a biosensor of the metabolite lactate combines an electron transporting polymer with lactate oxidase, which is the enzyme that specifically catalyzes the oxidation of lactate. Lactate is associated with ...

CryoEM study captures opioid signaling in the act

June 22, 2018

Opioid drugs like morphine and fentanyl are a mainstay of modern pain medicine. But they also cause constipation, are highly addictive, and can lead to fatal respiratory failure if taken at too high a dose. Scientists have ...

Researchers achieve unprecedented control of polymer grids

June 21, 2018

Synthetic polymers are ubiquitous—nylon, polyester, Teflon and epoxy, to name just a few—and these polymers are all long, linear structures that tangle into imprecise structures. Chemists have long dreamed of making polymers ...

Template to create superatoms could make for better batteries

June 21, 2018

Virginia Commonwealth University researchers have discovered a novel strategy for creating superatoms—combinations of atoms that can mimic the properties of more than one group of elements of the periodic table. These superatoms ...


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.