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

Eguether, Thibaut; Ermolaeva, Maria A.; Zhao, Yongge; Bonnet, Marion; Jain, Ashish; Pasparakis, Manolis; Courtois, Gilles; Tassin, Anne‐Marie

doi:10.1038/ncomms5585

Cited by 35 publications

(42 citation statements)

References 71 publications

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“…During the review of this manuscript, Eguether et al demonstrated by using transgenic mice carrying CYLD with a truncated deubiquitinase domain (CYLD ∆932 ), that CYLD was important for the formation of motile cilia in the mouse trachea [34]. In the present study, we show that CYLD knockout mice exhibit polydactyly and have defects in the formation of primary cilia in skin and kidney tissues and flagella in the testis, in addition to motile ciliary defects in the trachea.…”

Section: Discussionsupporting

confidence: 47%

CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6

et al. 2014

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Cilia are hair-like organelles extending from the cell surface with important sensory and motility functions. Ciliary defects can result in a wide range of human diseases known as ciliopathies. However, the molecular mechanisms controlling ciliogenesis remain poorly defined. Here we show that cylindromatosis (CYLD), a tumor suppressor protein harboring deubiquitinase activity, plays a critical role in the assembly of both primary and motile cilia in multiple organs. CYLD knockout mice exhibit polydactyly and various ciliary defects, such as failure in basal body anchorage and disorganization of basal bodies and axenomes. The ciliary function of CYLD is partially attributed to its deconjugation of the polyubiquitin chain from centrosomal protein of 70 kDa (Cep70), a requirement for Cep70 to interact with γ-tubulin and localize at the centrosome. In addition, CYLD-mediated inhibition of histone deacetylase 6 (HDAC6), which promotes tubulin acetylation, constitutes another mechanism for the ciliary function of CYLD. Small-molecule inhibitors of HDAC6 could partially rescue the ciliary defects in CYLD knockout mice. These findings highlight the importance of protein ubiquitination in the modulation of ciliogenesis, identify CYLD as a crucial regulator of this process, and suggest the involvement of CYLD deficiency in ciliopathies.

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Section: Discussionsupporting

confidence: 47%

CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6

et al. 2014

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“…Moreover, Cyld-knockout mice have strikingly different phenotypes than transgenic mice that carry truncations in the C-terminal deubiquitylase domain. For example, Cyld-knockout mice are viable, whereas C-terminal truncations of CYLD lead to embryonic lethality (Eguether et al, 2014;Jin et al, 2008;Lim et al, 2007;Massoumi et al, 2006;Reiley et al, 2006;Trompouki et al, 2009;Wright et al, 2007;Yang et al, 2014b;Zhang et al, 2006). In agreement with these findings, several studies have shown that the N-terminal CAP-Gly domains of CYLD mediate its interaction with microtubules and that these domains are required for its physiological and pathological functions.…”

Section: Introductionsupporting

confidence: 56%

“…Two teams have found that CYLD colocalizes with microtubules (Gao et al, 2008;Wickström et al, 2010), whereas other teams have shown that CYLD localizes primarily to the cytoplasm and spindle poles and only weakly colocalizes with microtubules (Eguether et al, 2014;Gomez-Ferreria et al, 2012;Urbe et al, 2012). Furthermore, Weisbrich et al have demonstrated that the conserved glycinelysine-asparagine-aspartate-glycine (GKNDG) motifs of CAP-Gly domains are responsible for their binding to the C-terminal EEY/F sequence motifs (Weisbrich et al, 2007).…”

Section: Cyld Interacts With Microtubulesmentioning

confidence: 99%

CYLD – a deubiquitylase that acts to fine-tune microtubule properties and functions

Yang

Zhou

2016

Journal of Cell Science

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Microtubules are dynamic structures that are crucially involved in a variety of cellular activities. The dynamic properties and functions of microtubules are regulated by various factors, such as tubulin isotype composition and microtubule-binding proteins. Initially identified as a deubiquitylase with tumor-suppressing functions, the protein cylindromatosis (CYLD) has recently been revealed to interact with microtubules, modulate microtubule dynamics, and participate in the regulation of cell migration, cell cycle progression, chemotherapeutic drug sensitivity and ciliogenesis. These findings have greatly enriched our understanding of the roles of CYLD in physiological and pathological conditions. Here, we focus on recent literature that shows how CYLD impacts on microtubule properties and functions in various biological processes, and discuss the challenges we face when interpreting results obtained from different experimental systems.

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“…At the same time, CYLD can also interact with several centrosomal proteins, such as CEP192 (Gomez-Ferreria et al, 2012), CAP350 (also known as CEP350) (Eguether et al, 2014) and CEP70 (Yang et al, 2014b), and this centrosomal pool of CYLD has been shown to regulate primary cilia formation and mitotic spindle assembly and/or orientation (Eguether et al, 2014;Gomez-Ferreria et al, 2012;Yang et al, 2014a,b). Similarly, USP15 deubiquitylates histone H2B in the nucleus (Long et al, 2014), prevents degradation of the transcriptional repressor RE1-silencing-transcription-factor (REST) at the ribosome (Faronato et al, 2013), as well as opposes RNF26-mediated ubiquitylation of p62 (also known as SQSTM1) at the ER, thus regulating the mobility of endosomes (Jongsma 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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The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells

Cited by 35 publications

References 71 publications

CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6

CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6

CYLD – a deubiquitylase that acts to fine-tune microtubule properties and functions

Mechanisms of regulation and diversification of deubiquitylating enzyme function

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