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Review
. 2019 Dec 20;47(6):1867-1879.
doi: 10.1042/BST20190527.

Ubiquitin-specific protease 8 (USP8/UBPy): a prototypic multidomain deubiquitinating enzyme with pleiotropic functions

Almut Dufner  1 , Klaus-Peter Knobeloch  1
Affiliations
Review

Ubiquitin-specific protease 8 (USP8/UBPy): a prototypic multidomain deubiquitinating enzyme with pleiotropic functions

Almut Dufner et al. Biochem Soc Trans. .

Abstract

Protein modification by ubiquitin is one of the most versatile posttranslational regulations and counteracted by almost 100 deubiquitinating enzymes (DUBs). USP8 was originally identified as a growth regulated ubiquitin-specific protease and is like many other DUBs characterized by its multidomain architecture. Besides the catalytic domain, specific protein-protein interaction modules were characterized which contribute to USP8 substrate recruitment, regulation and targeting to distinct protein complexes. Studies in mice and humans impressively showed the physiological relevance and non-redundant function of USP8 within the context of the whole organism. USP8 knockout (KO) mice exhibit early embryonic lethality while induced deletion in adult animals rapidly causes lethal liver failure. Furthermore, T-cell specific ablation disturbs T-cell development and function resulting in fatal autoimmune inflammatory bowel disease. In human patients, somatic mutations in USP8 were identified as the underlying cause of adrenocorticotropic hormone (ACTH) releasing pituitary adenomas causing Cushing's disease (CD). Here we provide an overview of the versatile molecular, cellular and pathology associated function and regulation of USP8 which appears to depend on specific protein binding partners, substrates and the cellular context.

Keywords: Cushings disease; DUBs; UBPy; USP8; isopeptidase; ubiquitin proteasome system.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Domain structures and protein interaction partners of USP8 and AMSH.
(A) Structure-function relationships of USP8 and interacting proteins and modules. The region affected by CD-causing mutations is depicted. (B) AMSH structure and interactions. ESCRT, Endosomal sorting complexes required for transport; FYVE, Zinc-binding domain that targets proteins to membrane lipids via interaction with phosphatidylinositol-3-phosphate, PI3P; VHS, Domain present in VPS-27, Hrs and STAM; MIT, microtubule interacting and transport; CBD, clathrin binding domain; JAMM, JAB1/MPN/Mov34 metalloenzyme; Rhod, rhodanese domain; UIM, ubiquitin interaction motif; CC, coiled-coil domain; NLS, nuclear localization signal.
Figure 2.
Figure 2.. Mechanism of USP8-mediated cortisol hyperproduction in CD.
14-3-3 proteins fail to bind mutant USP8 leading to cleavage and constitutive activation of USP8. USP8-mediated stabilization and activation of the EGFR ultimately leads to increased transcription of the gene encoding the ACTH precursor proopiomelanocortin (POMC) and the development of corticotroph adenoma. Chronic elevation of ACTH is followed by excessive adrenal glucocorticoid secretion. The stabilization and activation of additional receptor tyrosine kinases, of SMO or deubiquitination of unknown nuclear targets of USP8 may also be involved in enhanced POMC transcription.
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