Systematic survey of deubiquitinase localization identifies USP21 as a regulator of centrosome- and microtubule-associated functions

Urbé, Sylvie; Liu, Han; Hayes, Sebastian; Heride, Claire; Rigden, Daniel J.; Clague, Michael J.

doi:10.1091/mbc.e11-08-0668

Cited by 107 publications

(127 citation statements)

References 32 publications

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“…In the Cyld KO mice another DUB may compensate for the function of CYLD, whereas in the Cyld D932 mice the mutant CYLD protein probably acts as a dominant negative by delocalizing its substrate, thus preventing the action of the substitute DUB. USP 21 is a good candidate for carrying this function, as it has recently been shown to localize at the centrosome and affect primary cilia formation 50 . Moreover, it shares a similar target with CYLD in the regulation NF-kB signalling pathway 51 .…”

Section: Discussionmentioning

confidence: 99%

“…Finally, the E3 ubiquitin ligase MIB1 (ref. 56) was identified in a centrosome proteome 57 and the deubiquitinase USP21 is shown to be required for primary cilia formation 50 . In addition, another deubiquitinase Usp33 has recently been shown to localize at the centrosome by its binding with CP110 and its activity antagonizes SCF cyclinF ubiquitination of CP110 (ref.…”

Section: Discussionmentioning

confidence: 99%

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The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells

et al. 2014

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CYLD is a tumour suppressor gene mutated in familial cylindromatosis, a genetic disorder leading to the development of skin appendage tumours. It encodes a deubiquitinating enzyme that removes Lys63-or linear-linked ubiquitin chains. CYLD was shown to regulate cell proliferation, cell survival and inflammatory responses, through various signalling pathways. Here we show that CYLD localizes at centrosomes and basal bodies via interaction with the centrosomal protein CAP350 and demonstrate that CYLD must be both at the centrosome and catalytically active to promote ciliogenesis independently of NF-kB. In transgenic mice engineered to mimic the smallest truncation found in cylindromatosis patients, CYLD interaction with CAP350 is lost disrupting CYLD centrosome localization, which results in cilia formation defects due to impairment of basal body migration and docking. These results point to an undiscovered regulation of ciliogenesis by Lys63 ubiquitination and provide new perspectives regarding CYLD function that should be considered in the context of cylindromatosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells

et al. 2014

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“…Three systematic studies have mapped the subcellular distributions of human DUBs in cultured cells and the complement of DUBs found in Saccharomyces pombe (128,244,261). FIGURE 4B illustrates prominent subcellular sites of accumulation for individual mammalian DUBs, derived from these studies and from more specific investigations.…”

Section: Dubomicsmentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

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356

380

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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“…A computational analysis identified potential nuclear export signals (NESs) in many DUBs that would allow for their shuttling between the nucleus and cytosol (García-Santisteban et al, 2012), a prediction that has been experimentally validated for USP21 (García-Santisteban et al, 2012). Indeed, the presence of such a NES might account for the dual role of USP21 in regulating transcription via histone H2A deubiquitylation in the nucleus (Nakagawa et al, 2008) and in primary cilia formation and cilia-related Hedgehog signalling when it is localized to the centrosome (Heride et al, 2016;Urbe et al, 2012). In a similar manner, USP12 deubiquitylates histones H2A and H2B (Joo et al, 2011), but also translocates from the nucleus following T-cell receptor (TCR) stimulation to deubiquitylate and stabilize the TCR adaptor proteins linker for activation of T-cells family member 1 (LAT) and T-cell-receptor-associated-transmembrane-adapter-1 (TRAT1) at the cell surface (Jahan et al, 2016).…”

Section: Localization-dependent Dub Functionsmentioning

confidence: 99%

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Leznicki

Kulathu

2017

Journal of Cell Science

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Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes.This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: 'Exploitation of the host cell ubiquitin machinery by microbial effector proteins' by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985-1996. 'Cell scientist to watch -Mads Gyrd-Hansen' (J. Cell Sci. 130, 1981-1983.

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Systematic survey of deubiquitinase localization identifies USP21 as a regulator of centrosome- and microtubule-associated functions

Abstract: A localization atlas is provided for 66 of 90 mammalian GFP-tagged deubiquitinases (DUBs). USP21 is the only DUB in the panel that localizes to both microtubules and the centrosome. Functional data suggest a key role for USP21 in the choreography of microtubule reorganization.

Cited by 107 publications

References 32 publications

The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells

The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells

Deubiquitylases From Genes to Organism

Mechanisms of regulation and diversification of deubiquitylating enzyme function

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