Mutations in the polyglutamylase gene<i>TTLL5</i>, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility

Bedoni, Nicola; Haer‐Wigman, Lonneke; Vaclavik, Véronika; Tran, Viet H.; Farinelli, Pietro; Balzano, Sara; Royer‐Bertrand, Béryl; El‐Asrag, Mohammed E.; Bonny, Olivier; Ikonomidis, Christos; Litzistorf, Yan; Nikopoulos, Konstantinos; Yioti, Georgia G.; Stefaniotou, Maria; McKibbin, Martin; Booth, Adam; Ellingford, Jamie M; Black, Graeme C M; Toomes, Carmel; Inglehearn, Chris F.; Hoyng, Carel B.; Bax, Nathalie M.; Klaver, Caroline C.W.; Thiadens, Alberta A H J; Murisier, Fabien; Schorderet, Daniel F.; Ali, Manir; Cremers, Frans P.M.; Andréasson, Sten; Munier, Francis L.; Rivolta, Carlo

doi:10.1093/hmg/ddw282

Cited by 29 publications

(37 citation statements)

References 45 publications

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“…Alternatively, the absence of the deglutamylase CCP1 could have a stronger functional impact because this enzyme reverses the glutamylation generated by several polyglutamylases, each of them having a distinct function in photoreceptor cells. For example, the glutamylase TTLL5, which has been found mutated in human retinopathies (Bedoni et al, 2016), specifically modifies the X-linked protein RPGR. The massive degeneration of photoreceptors in the Ttll5 −/− mice was shown to result from the absence of glutamylation of RPGR rather than from aberrant tubulin glutamylation (Sun et al, 2016).…”

Section: Research Articlementioning

confidence: 99%

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: Research Articlementioning

confidence: 99%

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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“…It is very unlikely that DmTTLL5 possesses such transcriptional cofactor activity, as the protein does not contain this additional C-terminal domain (Supplementary Figure 1 ). It was recently found that mutations in human TTLL5 are associated with retinal dystrophy 52 , 53 , and two recent studies have identified the gene encoding retinitis pigmentosa GTPase regulator (RPGR) as a specific physiological substrate of mammalian TTLL5 54 , 55 . RPGR is one of the genes commonly mutated in retinitis pigmentosa, as RPGR mutations account for around 20% of all retinitis pigmentosa cases 56 .…”

Section: Discussionmentioning

confidence: 99%

Identification of DmTTLL5 as a Major Tubulin Glutamylase in the Drosophila Nervous System

Devambez

Dijk

Benlefki

et al. 2017

Sci Rep

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Microtubules (MTs) play crucial roles during neuronal life. They are formed by heterodimers of alpha and beta-tubulins, which are subjected to several post-translational modifications (PTMs). Amongst them, glutamylation consists in the reversible addition of a variable number of glutamate residues to the C-terminal tails of tubulins. Glutamylation is the most abundant MT PTM in the mammalian adult brain, suggesting that it plays an important role in the nervous system (NS). Here, we show that the previously uncharacterized CG31108 gene encodes an alpha-tubulin glutamylase acting in the Drosophila NS. We show that this glutamylase, which we named DmTTLL5, initiates MT glutamylation specifically on alpha-tubulin, which are the only glutamylated tubulin in the Drosophila brain. In DmTTLL5 mutants, MT glutamylation was not detected in the NS, allowing for determining its potential function. DmTTLL5 mutants are viable and we did not find any defect in vesicular axonal transport, synapse morphology and larval locomotion. Moreover, DmTTLL5 mutant flies display normal negative geotaxis behavior and their lifespan is not altered. Thus, our work identifies DmTTLL5 as the major enzyme responsible for initiating neuronal MT glutamylation specifically on alpha-tubulin and we show that the absence of MT glutamylation is not detrimental for Drosophila NS function.

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“…Among PTMs, polyglutamylation of α- or β-tubulin tails occurs most abundantly on stable MT structures such as the ones found in ciliary axoneme and neurons 2 , 3 . Its dysregulation causes impaired mucous flow 4 , male infertility 5 , retinal degeneration 6 , 7 , and aberrant ciliary beating 8 . Mislocalization of tubulin glutamylase TTLL6 is found in Joubert syndrome 9 .…”

Section: Introductionmentioning

confidence: 99%

Axoneme polyglutamylation regulated by Joubert syndrome protein ARL13B controls ciliary targeting of signaling molecules

et al. 2018

Nat Commun

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Tubulin polyglutamylation is a predominant axonemal post-translational modification. However, if and how axoneme polyglutamylation is essential for primary cilia and contribute to ciliopathies are unknown. Here, we report that Joubert syndrome protein ARL13B controls axoneme polyglutamylation, which is marginally required for cilia stability but essential for cilia signaling. ARL13B interacts with RAB11 effector FIP5 to promote cilia import of glutamylase TTLL5 and TTLL6. Hypoglutamylation caused by a deficient ARL13B-RAB11-FIP5 trafficking pathway shows no effect on ciliogenesis, but promotes cilia disassembly and, importantly, impairs cilia signaling by disrupting the proper anchoring of sensory receptors and trafficking of signaling molecules. Remarkably, depletion of deglutamylase CCP5, the predominant cilia deglutamylase, effectively restores hypoglutamylation-induced cilia defects. Our study reveals a paradigm that tubulin polyglutamylation is a major contributor for cilia signaling and suggests a potential therapeutic strategy by targeting polyglutamylation machinery to promote ciliary targeting of signaling machineries and correct signaling defects in ciliopathies.

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Mutations in the polyglutamylase geneTTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility

Cited by 29 publications

References 45 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

Identification of DmTTLL5 as a Major Tubulin Glutamylase in the Drosophila Nervous System

Axoneme polyglutamylation regulated by Joubert syndrome protein ARL13B controls ciliary targeting of signaling molecules

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