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USP8 gene
URL of this page: https://medlineplus.gov/genetics/gene/usp8/

USP8 gene

ubiquitin specific peptidase 8

Normal Function

The USP8 gene provides instructions for making an enzyme that removes molecules called ubiquitin from certain proteins. Within cells, damaged or excess proteins are tagged with ubiquitin, which serves as a signal that the protein should be broken down (metabolized). When the USP8 enzyme removes ubiquitin from a protein, it prevents that protein from being metabolized. As a result, USP8 is known as a rescue protein.

The USP8 enzyme is thought to play an important role in normal cell growth and division. The enzyme is especially important for cell structures called endosomes, which help sort and transport molecules within the cell. Within the endosome, the USP8 enzyme plays a key role in regulating the transport of a protein called epidermal growth factor receptor (EGFR) protein. This receptor protein is part of an important signaling pathway that is involved in processes such as cell growth and division (proliferation) and cell survival. The USP8 enzyme helps regulate the activity of the EGFR protein by preventing its metabolism.

Health Conditions Related to Genetic Changes

Cushing disease

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the USP8 gene have been found in noncancerous (benign) pituitary tumors (also called adenomas) from patients with Cushing disease. This condition is characterized by high levels of the hormone cortisol in the blood and is a specific type of Cushing syndrome. Although the high levels of cortisol in people with Cushing syndrome can be caused by many different factors, the high levels of cortisol in people with Cushing disease are caused by pituitary adenomas. In some people with Cushing disease, pituitary adenomas contain cells with a pathogenic variant in the USP8 gene.

The pathogenic variants that cause Cushing disease are typically somatic, which means that they are acquired during a person's lifetime and are present only in certain cells. Somatic variants in the USP8 gene are the most common genetic cause of Cushing disease. These USP8 variants cause cells in the pituitary adenoma to produce a version of the USP8 enzyme that does not switch off properly. As a result, the EGFR signaling pathway becomes overactive, causing cells within the adenoma to release too much of a hormone called adrenocorticotropic hormone (ACTH). The higher levels of ACTH released by the pituitary adenoma cause the adrenal glands to release too much cortisol, which leads to the signs and symptoms seen in people with Cushing disease.

More About This Health Condition

Other Names for This Gene

  • HumORF8
  • KIAA0055
  • SPG59
  • ubiquitin carboxyl-terminal hydrolase 8
  • ubiquitin isopeptidase Y
  • UBPY

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Kairys N, Anastasopoulou C, Schwell A. Cushing Disease. 2023 Feb 27. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK448184/ Citation on PubMed
  • Kakihara K, Asamizu K, Moritsugu K, Kubo M, Kitaguchi T, Endo A, Kidera A, Ikeguchi M, Kato A, Komada M, Fukushima T. Molecular basis of ubiquitin-specific protease 8 autoinhibition by the WW-like domain. Commun Biol. 2021 Nov 8;4(1):1272. doi: 10.1038/s42003-021-02802-x. Citation on PubMed
  • Perez-Rivas LG, von Selzam V, Sharma P, Reincke M, Theodoropoulou M. Prevalence and clinical associations of USP8 variants in corticotroph tumours: a systematic review and aggregate data meta-analysis of 2171 cases. Eur J Endocrinol. 2025 May 30;192(6):S41-S52. doi: 10.1093/ejendo/lvaf097. Citation on PubMed
  • Rebollar-Vega RG, Zuarth-Vazquez JM, Hernandez-Ramirez LC. Clinical Spectrum of USP8 Pathogenic Variants in Cushing's Disease. Arch Med Res. 2023 Dec;54(8):102899. doi: 10.1016/j.arcmed.2023.102899. Epub 2023 Nov 2. Citation on PubMed
  • Simon J, Theodoropoulou M. Genetics of Cushing's disease. J Neuroendocrinol. 2022 Aug;34(8):e13148. doi: 10.1111/jne.13148. Epub 2022 May 21. Citation on PubMed
  • Theodoropoulou M, Reincke M. Genetics of Cushing's disease: from the lab to clinical practice. Pituitary. 2022 Oct;25(5):689-692. doi: 10.1007/s11102-022-01253-9. Epub 2022 Jul 19. Citation on PubMed
  • Wanichi IQ, de Paula Mariani BM, Frassetto FP, Siqueira SAC, de Castro Musolino NR, Cunha-Neto MBC, Ochman G, Cescato VAS, Machado MC, Trarbach EB, Bronstein MD, Fragoso MCBV. Cushing's disease due to somatic USP8 mutations: a systematic review and meta-analysis. Pituitary. 2019 Aug;22(4):435-442. doi: 10.1007/s11102-019-00973-9. Citation on PubMed
  • Zhang Q, Cai Y, Liu Y, Yao B, Sharma P, Ruoff E, Ma Z, Zopp S, Wu Y, Abreu AP, Zhang S, Tichomirowa MA, Wang Y, Stalla G, Qiao N, Ye Z, Hanzu FA, Chen H, Buchfelder M, Yao Z, Flitsch J, Li Y, Thorsteinsdottir J, Wang Y, Nasi-Kordhishti I, Ye H, Honegger J, Sbiera S, Kaiser UB, Fassnacht M, Zhang Z, Reincke M, Theodoropoulou M, Zhao Y, Perez-Rivas LG. Risk of recurrence after successful surgery for Cushing's disease and association with USP8 genotype and tumour size: an international, retrospective, longitudinal cohort study. Lancet Diabetes Endocrinol. 2026 Apr;14(4):327-336. doi: 10.1016/S2213-8587(25)00396-1. Epub 2026 Mar 2. Citation on PubMed

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