The molecular mechanism underlying enzyme activity regulation of ubiquitin-specific protease 8 (USP8) has been decoded by researchers at Tokyo Tech. USP8 has been implicated in Cushing's disease pathogenesis. They have identified an autoinhibitory region on the enzyme that interacts with its catalytic region. They also provide first evidence on the release of autoinhibition due to USP8 mutations as the underlying cause behind Cushing's disease. Their findings could be invaluable for understanding Cushing's disease pathogenesis.