La FAM fatale: USP9X in development and disease

Abstract

Deubiquitylating enzymes (DUBs), act downstream of ubiquitylation. As such, these post-post-translational modifiers function as the final arbitrators of a protein substrate’s ubiquitylation status, thus regulating its fate. In most instances, DUBs moderate the absolute level of a substrate, its locality or activity, rather than being an “all-or-none” phenomenon. Yet, disruption of this quantitative regulation can produce dramatic qualitative differences. The ubiquitin-specific protease 9X (USP9X/FAM) is a substrate-specific DUB, which displays an extraordinarily high level of sequence conservation from Drosophila to mammals. It is primarily the recent revelations of USP9X’s pivotal role in human cancers, both as oncogene or tumour suppressor, in developmental disorders including intellectual disability, epilepsy, autism and developmental delay that has led to a subsequent re-examination of its molecular and cellular functions. Results from experimental animal models have implicated USP9X in neurodegeneration, including Parkinson’s and Alzheimer’s disease, as well as autoimmune diseases. In this review, we describe the current and accumulated knowledge on the molecular, cellular and developmental aspects of USP9X function within the context of the biological consequences during normal development and disease.

USP9X deletion elevates the density of oligodendrocytes within the postnatal dentate gyrus

“…10 How could the loss of Usp9x culminate in oligodendrogenesis? At this stage this is unclear, however previous reports of interactions between USP9X and members of the Notch signaling pathway, 29 coupled with the reduced expression of Notch pathway members revealed here (Hes5, Fabp7 and Tnc) suggests that a primary role for USP9X, in the context of NSCs, is the maintenance of their identity and self-renewal capacity. Identification of why the loss of Usp9x potentially biases NSCs toward oligodendrocytic differentiation will require a more comprehensive analysis of the USP9X interactome, coupled with proteomic analysis of NSCs lacking this enzyme.…”

USP9X regulates centrosome duplication and promotes breast carcinogenesis

“…We showed that the physical association of USP9X with centrosomes is cell cycle-dependent and mostly detected in S and G 2 phases. Remarkably, disrupting protein trafficking or the Golgi in polarized epithelia results in relocation or accumulation of USP9X, suggesting that this protein shuttles between a number of organelles and vesicles52. These observations highlight the need to interrogate USP9X–substrate interactions with approaches sorting specific subcellular compartments instead of more disruptive biochemical methods that extensively destroy cellular architectures52.…”

The Deubiquitinase USP9X Maintains DNA Replication Fork Stability and DNA Damage Checkpoint Responses by Regulating CLASPIN during S-Phase

“…USP9X is involved in the regulation of cell adhesion molecules such as E-cadherin, chromosome segregation, NOTCH, and TGFb signaling as well as apoptosis (comprehensively reviewed in ref. 30).…”

“…In different cancers, USP9X can act as an oncogene or as a tumor suppressor gene in a context-dependent manner: USP9X is overexpressed in multiple carcinomas including lymphomas, nonsmall cell lung and breast cancer (30). The best described oncogenic function of USP9X derives from its role in promoting the deubiquitinylation and stabilization of antiapoptotic protein MCL1.…”