Probing the dysregulation of ubiquitin-specif


Probing-the-dysregulation-of-ubiquitin-specif.png

Image: Mutations of the enzyme ubiquitin-specific protease 8 (USP8) in the pituitary adenoma lead to excessive secretion of the adrenocorticotropic hormone (ACTH), which stimulates cortisol production - the hallmark of Cushing's disease. This affects important organs and tissues in the body and, if left untreated, can lead to serious complications. Little is known about the details of the effects of these mutations on USP8 function. Tokyo Tech researchers in Japan have now linked the dysregulation of USP8 to the pathogenesis of Cushing's disease. outlook more

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The molecular mechanism underlying the regulation of the enzyme activity of the ubiquitin-specific protease 8 (USP8) has been deciphered by researchers at Tokyo Tech. USP8 has been implicated in the pathogenesis of Cushing's disease. They identified an autoinhibitory region of the enzyme that interacts with its catalytic region. They also provide initial indications of the release of auto-inhibition by USP8 mutations as a cause of Cushing's disease. Your results could be invaluable in understanding the pathogenesis of Cushing's disease.

Cushing's disease, caused by an excess of the steroid hormone cortisol in the body (Figure 1), affects thousands of people worldwide and is the subject of extensive medical research. Developing a targeted therapy for the treatment of Cushing's disease would require a thorough understanding of the underlying molecular mechanisms. At the molecular level, mutations in ubiquitin-specific protease 8 (USP8), a deubiquitinizing enzyme that cleaves ubiquitin from proteins, have been implicated in the pathogenesis of Cushing's disease.

USP8 normally binds to a class of adapter proteins called 14-3-3 to be inhibited. Mutations of USP8 in Cushing's disease remove this binding of USP8 to 14-3-3, resulting in excessive secretion of the adrenocorticotropic hormone that stimulates cortisol production - the hallmark of Cushing's disease. Little is known, however, about the details of the effects of these mutations on USP8 function.

To this end, a group of researchers from the Tokyo Institute of Technology (Tokyo Tech) studied the molecular structure and functioning of USP8 in depth, hoping to find therapeutic targets against Cushing's disease. The motivation behind her study explains Dr. Toshiaki Fukushima, Assistant Professor at the Cell Biology Center, Institute of Innovative Research at Tokyo Tech, who led the study: “We were already investigating the role of the mutated USP8 in Cushing's disease. Understanding the effects of mutations on activity regulation was of course the next step in our research. "

The researchers found that wild-type USP8 possessed a unique amino acid region from position 645 to 684 within its 1118 residue amino acid sequence that exhibited autoinhibitory properties (Figure 2). It was found that this region forms a WW-like domain structure. To explore this further, they performed biochemical analyzes, including fluorescence resonance energy transfer measurements and docking simulations in silico, and observed that the WW-like domain binds to the catalytic domain of USP8 to provide the entrance to the ubiquitin- constricting binding pocket that forms an essential point in the deubiquitinating response of USP8.

Next, the researchers found that the inhibition of USP8 activity mediated by 14-3-3 proteins was achieved in part by enhancing the interaction between the WW-like domain and the catalytic domain. In addition, they analyzed the effects of pathogenic mutations in USP8. The mutations were found to break the binding of USP8 to 14-3-3, as observed by the researchers in their previous experiment, suppress the interaction between the WW-like and catalytic domains, and exacerbate the deubiquitinous activity of USP8 . has led (Figure 3).

These results were published as a research article in Communications Biology.

Overall, the researchers seem to have deciphered what constitutes the regulation of USP8 enzyme activity and how it is dysregulated in Cushing's disease. Whether hyperactivated USP8 would serve as a therapeutic target for Cushing's disease warrants further research. In this context, Dr. Fukushima: “Our study on USP8 is perhaps a stepping stone to the development of a targeted therapy for Cushing's disease. We hope that our work will not only be based on our new knowledge, but also stimulate similar research. "

The findings of this study promise hope for both medical researchers and patients with Cushing's disease.

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About the Tokyo Institute of Technology

Tokyo Tech is at the forefront of research and higher education as the leading science and technology university in Japan. Tokyo Tech researchers excel in areas that range from materials science to biology, computer science and physics. Tokyo Tech was founded in 1881 and is home to over 10,000 undergraduate and graduate students annually who develop into scientific leaders and some of the most sought-after engineers in the industry. The Tokyo Tech community embodies the Japanese philosophy of "Monotsukuri," which means "technical ingenuity and innovation," and seeks to contribute to society through effective research.

https://www.titech.ac.jp/english/

About Dr. Toshiaki Fukushima

Dr. Toshiaki Fukushima is Assistant Professor at the Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Japan. Dr. Fukushima is an expert in the field of ubiquitin biology, tumorigenesis and the signaling of growth factors. He is currently associated with the institute's Komada Laboratory. He received his PhD in Agriculture from Tokyo University in 2005. He has written major research publications on his subject areas in national and international journals.

diary

Communication biology

Research method

Experimental study

Research subject

Cells

Article heading

Molecular basis of ubiquitin-specific protease-8 autoinhibition by the WW-like domain

Publication date of the article

November 8, 2021

COI declaration

The authors do not declare any competing interests.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of press releases sent to EurekAlert! by contributing institutions or for the use of information via the EurekAlert system.


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