Study Sheds Light on Effects of USP8 Mutations on Disease Development

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by Marta Figueiredo, PhD |

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Scientists have decoded molecular processes of a gene whose defects are implicated in Cushing’s disease and some cancers.

Their study found that mutations in the ubiquitin-specific protease 8 (USP8) gene prevent a self-suppressing mechanism of the resulting enzyme, leading to its overactivation. Overactivation of this enzyme has been shown to cause abnormal cell growth in cancer tumors with USP8 mutations.

The new findings provide further insights on the molecular mechanisms behind that overactivation, which can potentially identify therapeutic targets for Cushing’s disease, the researchers said.

“We were already exploring the role of mutated USP8 in Cushing’s disease. Understanding the effects of mutations on its activity regulation was naturally the next step in our research,” Toshiaki Fukushima, PhD, the study’s co-senior author, said in a press release.

“Our study regarding USP8 is perhaps a stepping-stone to developing targeted therapy against Cushing’s disease,” added Fukushima, who is an assistant professor at the Institute of Innovative Research’s Cell Biology Center at Tokyo Institute of Technology (Tokyo Tech) in Japan.

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“Besides developing on our novel findings, we hope that our work will inspire similar research as well,” Fukushima said.

The study, “Molecular basis of ubiquitin-specific protease 8 autoinhibition by the WW-like domain,” was published in the journal Communications Biology.

Cushing’s disease is caused by a tumor in the brain’s pituitary gland that increases the release of adrenocorticotropic hormone, which stimulates cortisol production by the adrenal glands, located above the kidneys. Abnormally high cortisol levels are ultimately responsible for most Cushing’s symptoms.

Mutations in the USP8 gene, which provides instructions to produce an enzyme of the same name, have been identified in tumors of about half of Cushing’s disease patients.

USP8 regulates the stability and turnover of proteins involved in key cellular processes, such as cell growth and DNA repair, by removing a chemical modification called ubiquitin that typically works as a marker for degradation.

USP8 mutations in Cushing’s are known to make USP8 overactive by preventing the enzyme from binding to its natural suppressor, a protein called 14-3-3. USP8 overactivation promotes signaling via EGFR, a receptor that drives the growth of some types of cancer cells.

However, “the molecular basis of 14-3-3-dependent inhibition of USP8’s enzyme activity remains unclear,” the researchers wrote.

To address this, Fukushima and colleagues at Tokyo Tech and Yokohama City University analyzed the effects of several USP8 mutations in the structure, activity, and interactions of the resulting enzyme.

They found that besides 14-3-3-dependent block, USP8 has a self-suppressing mechanism that involves a region of the enzyme that forms a specific structure, called WW-like domain.

This WW-like domain binds to another domain, called the catalytic domain, narrowing the pocketlike region in which ubiquitin enters, to be removed from the target protein and ultimately suppressing USP8’s ability to exert its action.

Further analysis showed that the 14-3-3 protein blocks the activity of USP8 partly by boosting the interaction between the enzyme’s WW-like and catalytic domains.

In addition, Ser718 deletion, a common USP8 mutation in Cushing’s disease, was found to prevent USP8’s binding to 14-3-3 and to “significantly, but incompletely, [suppress] the interaction between the WW-like and [catalytic] domains,” the researchers wrote.

These results highlight that USP8 has a self-suppressing mechanism that is affected by mutations associated with Cushing’s disease, leading to the enzyme’s overactivation and thereby promoting abnormal cell growth.

By discovering USP8’s self-regulatory mechanism and the key regions involved in it, these findings may help identify potential therapeutic targets for Cushing’s disease caused by USP8 mutations.

“Further studies will be required to determine the physiological and [disease-associated] significance of this regulatory mechanism of USP8,” the researchers wrote.