Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon

Rocha, Cecilia; Papon, Laura; Cacheux, Wulfran; Sousa, Patricia; Lascano, Valeria; Tort, Olivia; Giordano, Tiziana; Vacher, Sophie; Lemmers, Bénédicte; Mariani, Pascale; Meseure, Didier; Medema, Jan Paul; Bièche, Ivan; Hahne, Michael; Janke, Carsten

doi:10.15252/embj.201488466

Cited by 103 publications

(108 citation statements)

References 48 publications

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“…As glycylation in the mouse retina is catalysed exclusively by TTLL3, we investigated the role of this PTM in our TTLL3-knockout (Ttll3 −/− ) mouse (Bosch Grau et al, 2013;Rocha et al, 2014). We first confirmed the absence of TTLL3 expression in retina of Ttll3 −/− mice at different developmental stages, and demonstrated that TTLL8 expression remained virtually undetectable, similar to in the wild-type situation (Fig.…”

Section: Absence Of Tubulin Glycylation Leads To Hyperglutamylation Imentioning

confidence: 78%

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration

Grau

Masson

Gadadhar

et al. 2017

Journal of Cell Science

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Tubulin is subject to a wide variety of posttranslational modifications, which, as part of the tubulin code, are involved in the regulation of microtubule functions. Glycylation has so far predominantly been found in motile cilia and flagella, and absence of this modification leads to ciliary disassembly. Here, we demonstrate that the correct functioning of connecting cilia of photoreceptors, which are nonmotile sensory cilia, is also dependent on glycylation. In contrast to many other tissues, only one glycylase, TTLL3, is expressed in retina. Ttll3−/− mice lack glycylation in photoreceptors, which results in shortening of connecting cilia and slow retinal degeneration. Moreover, absence of glycylation results in increased levels of tubulin glutamylation in photoreceptors, and inversely, the hyperglutamylation observed in the Purkinje cell degeneration ( pcd) mouse abolishes glycylation. This suggests that both posttranslational modifications compete for modification sites, and that unbalancing the glutamylation-glycylation equilibrium on axonemes of connecting cilia, regardless of the enzymatic mechanism, invariably leads to retinal degeneration.

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Section: Absence Of Tubulin Glycylation Leads To Hyperglutamylation Imentioning

confidence: 78%

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration

Grau

Masson

Gadadhar

et al. 2017

Journal of Cell Science

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“…Since TTLL10 is inactive in humans, human sperm flagellar tubulins are monoglycylated [54], and the absence of long chain polyglycylation does not affect ciliary motility [56], so the functional significance of extended polyglycine chains is uncertain. However, a knockout of TTLL3 eliminates all tubulin glycylation in the colon, where TTLL3 is the only glycylase expressed [57]. This absence of glycylation led to reductions in primary cilia and enhanced carcinogenesis in the colon, suggesting that glycylation of tubulin may play a role in the maintenance of primary cilia and cell proliferation.…”

Section: Polyglutamylation and Polyglycylation Of Tubulin In Mtsmentioning

confidence: 99%

Post-translational modifications of tubulin: pathways to functional diversity of microtubules

Song

Brady

2015

Trends in Cell Biology

336

305

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Tubulin and microtubules are subject to a remarkable number of posttranslational modifications. Understanding the roles these modifications play in determining functions and properties of microtubules has presented a major challenge that is only now being met. Many of these modifications are found concurrently, leading to considerable diversity in cellular microtubules, which varies with development, differentiation, cell compartment and cell cycle. We now know that posttranslational modifications of tubulin affect not only the dynamics of the microtubules, but also their organization and interaction with other cellular components. Many early suggestions of how posttranslational modifications affect microtubules have been replaced with new ideas and even new modifications as our understanding of cellular microtubule diversity comes into focus.

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“…Monoglycylation is ubiquitous in ciliated tissues, whereas only a subset contains polyglycylated microtubules (61). Glycylation is important for the stability, length, and function of motile cilia (7,62,63), the formation and maintenance of primary cilia, and control of cell proliferation (64).…”

Section: Glycylationmentioning

confidence: 99%

Writing and Reading the Tubulin Code

Garnham

Roll-Mecak

2015

Journal of Biological Chemistry

179

180

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Microtubules give rise to intracellular structures with diverse morphologies and dynamics that are crucial for cell division, motility, and differentiation. They are decorated with abundant and chemically diverse posttranslational modifications that modulate their stability and interactions with cellular regulators. These modifications are important for the biogenesis and maintenance of complex microtubule arrays such as those found in spindles, cilia, neuronal processes, and platelets. Here we discuss the nature and subcellular distribution of these posttranslational marks whose patterns have been proposed to constitute a tubulin code that is interpreted by cellular effectors. We review the enzymes responsible for writing the tubulin code, explore their functional consequences, and identify outstanding challenges in deciphering the tubulin code.Microtubules are non-covalent cylindrical polymers formed by ␣␤-tubulin heterodimer building blocks. They possess two seemingly contradictory properties; they are highly dynamic, exhibiting rapid growth and shrinkage of their ends (1), but are also very rigid, with persistence lengths on the order of cellular dimensions (2). This duality is thought to underlie the versatile architectures of microtubule networks in cells ( Fig. 1) and is tuned by a myriad of cellular effectors. These fall into two categories: effectors that bind to the microtubule and alter its properties non-covalently (motors and microtubule-associated proteins (MAPs)) 2 and effectors that chemically modify the tubulin subunits (tubulin posttranslational modification enzymes). Although the field has made tremendous progress in recent decades identifying a compendium of microtubule-interacting proteins and understanding their interplay and regulation in the cell, we are just now starting to unravel the basic mechanisms used by cells to chemically modify microtubules, despite the fact that tubulin posttranslational modifications have been known for over 40 years. A renaissance of interest into the roles of tubulin posttranslational modifications has been precipitated by the discovery in the last few years of the enzymes responsible for these modifications (3-8), methods for producing unmodified (9, 10), engineered, (11, 12) as well as chemically defined modified tubulin (13), and developments and refinements of in vitro microtubule-based assays using high-resolution microscopy and microfabricated substrates (14 -16).Tubulin posttranslational modifications are chemically diverse, ranging from phosphorylation (17), acetylation (18,19), palmitoylation (20), sumoylation (21), polyamination (22), and S-nitrosylation (23) to tyrosination (24), glutamylation (25, 26), and glycylation (27). Most of these modifications are reversible. Tubulin posttranslational modifications are evolutionarily conserved and abundantly represented in cellular microtubules. Most importantly, their distribution is stereotyped in cells. For example, interphase microtubules are enriched in tyrosination (28), whereas kinetochore fibers a...

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Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon

Cited by 103 publications

References 48 publications

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration

Post-translational modifications of tubulin: pathways to functional diversity of microtubules

Writing and Reading the Tubulin Code

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