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

Almut Dufner,Klaus-Peter Knobeloch

doi:10.1042/bst20190527

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.

Highlights

The modification of proteins with the 76-amino-acid peptide ubiquitin represents perhaps the most versatile posttranslational modification system with innumerable layers of complexity and regulation [1]
The finding that mutations in USP8 are associated with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas in Cushing’s disease (CD) has recently drawn much attention [10,11]
USP8 contains an N-terminal microtubule interacting and transport (MIT) domain which has unveiled its potential to interact with CHMP proteins, components of the endosomal sorting complexes required for transport (ESCRT) III [12] (Figure 1A)

Summary

Introduction

The modification of proteins with the 76-amino-acid peptide ubiquitin represents perhaps the most versatile posttranslational modification system with innumerable layers of complexity and regulation [1]. Besides the EGFR, the ubiquitination, endosomal lysosomal trafficking, and/or stability of many other transmembrane proteins have been shown to be regulated by USP8.

Results

Conclusion