Tubulin acetylation: responsible enzymes, biological functions and human diseases

Li, Lin; Yang, Xiang-Jiao

doi:10.1007/s00018-015-2000-5

Cited by 222 publications

(204 citation statements)

References 203 publications

(444 reference statements)

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“…CK2 was shown to increase HDAC6 activity either by direct HDAC6 phosphorylation (46) or by priming GSK3β, which interacts with HDAC6 and enhances its activity by increasing HDAC6 phosphorylation at Ser22 (45). Acetylation of α-tubulin contributes to microtubule stability, and α-tubulin deacetylation via increased HDAC activity was suggested to lead to microtubule instability and cell motility (44,45). Along this line, a recent work in a mouse model of familial dysautonomia showed that reduced levels of IκB kinase complex-associated protein (IKAP) lead to increased HDAC6 levels in sensory neurons, thereby reducing acetylated α-tubulin and provoking microtubule instability (56).…”

Section: Discussionmentioning

confidence: 99%

“…These results indicate that the homeostatic changes in AIS induced by sustained M-current inhibition were independent of L-type Ca 2+ channel activity but were contingent on the crucial AIS component, protein kinase CK2. Recent studies suggest that CK2 leads to microtubule destabilization and stimulates microtubule dynamics by increasing the activity of the tubulin deacetylase HDAC6 (44)(45)(46). Thus, we checked the impact of 100 nM taxol, a microtubule stabilizer, on the distal redistribution of FGF14 induced by 4 h of XE991 exposure.…”

Section: Inhibition Of Ck2 Prevents the Adaptive Changes In Intrinsicmentioning

confidence: 99%

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M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

Lezmy

Lipinsky

Khrapunsky

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Alterations in synaptic input, persisting for hours to days, elicit homeostatic plastic changes in the axon initial segment (AIS), which is pivotal for spike generation. Here, in hippocampal pyramidal neurons of both primary cultures and slices, we triggered a unique form of AIS plasticity by selectively targeting M-type K + channels, which predominantly localize to the AIS and are essential for tuning neuronal excitability. While acute M-current inhibition via cholinergic activation or direct channel block made neurons more excitable, minutes to hours of sustained M-current depression resulted in a gradual reduction in intrinsic excitability. Dual soma-axon patch-clamp recordings combined with axonal Na + imaging and immunocytochemistry revealed that these compensatory alterations were associated with a distal shift of the spike trigger zone and distal relocation of FGF14, Na + , and K v 7 channels but not ankyrin G. The concomitant distal redistribution of FGF14 together with Na v and K v 7 segments along the AIS suggests that these channels relocate as a structural and functional unit. These fast homeostatic changes were independent of L-type Ca 2+ channel activity but were contingent on the crucial AIS protein, protein kinase CK2. Using compartmental simulations, we examined the effects of varying the AIS position relative to the soma and found that AIS distal relocation of both Na v and K v 7 channels elicited a decrease in neuronal excitability. Thus, alterations in M-channel activity rapidly trigger unique AIS plasticity to stabilize network excitability.homeostatic plasticity | axon initial segment | M-current | potassium channel | K v 7

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Section: Discussionmentioning

confidence: 99%

Section: Inhibition Of Ck2 Prevents the Adaptive Changes In Intrinsicmentioning

confidence: 99%

M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

Lezmy

Lipinsky

Khrapunsky

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…3,4 Changes in tubulin post-translational modifications have been associated with neurodegenerative disorders, cancer, heart diseases and other pathological conditions. 5,6 Stable microtubules are well known to contain acetylated tubulin, which is one of the major post-translational modifications of microtubules. Acetylation tubulin has been implicated in the differentiation of microtubule structure and function.…”

Section: Introductionmentioning

confidence: 99%

Expression of acetylated tubulin in the postnatal developing mouse cochlea

Liu¹,

Wang²,

Yu³

et al. 2018

Eur J Histochem

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Microtubules are an essential component of the cytoskeleton of a eukaryotic cell. The post-translational tubulin modifications play an important role in regulating microtubule properties, acetylation tubulin is one of the major post-translational modifications of microtubules. Acetylation tubulin has also been shown to be expressed in the cochlea. However, the detailed expression profiles of acetylation tubulin protein during development have not yet been investigated in the postnatal mammalian cochlea. Here, we first examined the spatio-temporal expression of acetylated tubulin in the mouse cochlea during postnatal development. At postnatal day 1 (P1), acetylated tubulin was localized primarily to the auditory nerve inside the cochlea and their synaptic contacts with the inner and outer hair cells (IHCs and OHCs). In the organ of Corti, acetylated tubulin occurred first at the apex of pillar cells. At P5, acetylated tubulin first appeared in the phalangeal processes of Deiters’ cells. At P8, staining was maintained in the phalangeal processes of Deiters’ cells and neural elements. At P10, labeling in Deiters’ cells extended from the apices of OHCs to the basilar membrane, acetylated tubulin was expressed throughout the cytoplasm of inner and outer pillar cells. At P12, acetylated tubulin displayed prominent and homogeneous labeling along the full length of the pillar cells. Linear labeling was present mainly in the Deiters’ cell bodies underlying OHCs. Between P14 and P17, acetylated tubulin was strongly expressed in inner and outer pillar cells and Deiters’ cells in a similar pattern as observed in the adult, and labeling in these cells were arranged in bundles. In addition, acetylated tubulin was expressed in stria vascularis, root cell bodies, and a small number of fibrocytes of the spiral ligament until the adult. In the adult mouse cochlea, immunostaining continued to predominate in Deiters’ cells and pillar cells. In Deiters’ cells, immunolabeling formed cups securing OHCs basal portions, and continued presence of acetylated tubulin-labeled nerve terminals below IHCs was shown. Our results presented here underscored the essential role played by acetylated tubulin in postnatal cochlear development, auditory neurotransmission and cochlear mechanics.

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“…Interestingly, tubulin PTMs are potential regulators of this process as much as, for long time, acetylated MTs were referred almost synonymously to old and stable MTs. Indeed, among its several biological functions [14], it has been shown that acetylation accumulates during MT aging and it has been proposed that the MT-acetylase α Tubulin Acetyl Transferase1 (αTAT1) can act as a clock for MT lifetimes [15], due to its preference for MTs and its low catalytic rate. Nevertheless, other candidates may be responsible for minor tubulin acetylation in vivo, including Elongator Complex Protein Elp3, which acts as tubulin acetylase, controlling the development and the migration of cortical neurons [16].…”

mentioning

confidence: 99%

“…A reliable alternative can be the fine modulation of MT acetylation, which seems to be tightly associated to axonal transport and locomotor defects [16,36,38]. Since the extent of MT acetylation depends on the balance of the antagonistic acetylases and deacetylases activities, its modulation can be achieved by the use of specific stimulators or inhibitors of αTAT1 or Histone Deacetylase 6 (HDAC6) [14]. The latter specifically acts on tubulin [40], and its inhibition exerts neuroprotection in many age-related neurodegenerative disorders [41] and rescues the transport defects observed in Huntington's disease [37].…”

mentioning

confidence: 99%

Is the Regulation of Microtubule Stability at the Crossroad Between Aging and Disease of Dopaminergic neurons?

Cartelli¹

2017

AND

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Microtubules (MTs) are built up by αβ tubulin dimers, which assemble into non-covalent polymers with an intrinsic resistance to bending and compression and capable to alternate slow polymerizing phases to rapid shrinking ones, a behaviour called "dynamic instability" [1]. The proper regulation of MT stability (i.e., more stable MTs display a longer half-life) is fundamental for the development, the survival and the aging of neurons, since both hyper-stable and overly dynamic MTs affect neuronal functions eventually leading to cell death [2]. α and β tubulin Posttranslational Modifications (PTMs) mark dynamic or stable MTs, which are found in specific neuronal compartments and whose stability changes during neuronal differentiation and aging [3]. Indeed, tyrosinated α tubulin is associated to highly dynamic MTs, which are abundant in young neurons and at the presynaptic bouton of mature neurons. During neuronal maturation MT stability increases and MTs inside the axonal shaft accumulate PTMs which extend their half-life, either through a direct stabilization of the MT lattice [4] or by governing upstream events, such as the recruitment of MT-interacting protein [5] or by protecting MTs from depolymerizing kinesins and severing enzymes [6,7]. Nevertheless, the stability of MTs has to be maintained under a physiological threshold, since their excessive stabilization can eventually lead to MT bundling and block of axonal transport [8]. As many of the axonal MTs are long-lived polymers which persist for the entire life of the neuron, their aging is a critical event which potentially impacts on the neuron lifespan. Indeed, MTs are structures with an intrinsic self-repair capability [9] but, due to defects accumulated during growth [10] and to their ends which become more tapered during time [11], the older MTs are more susceptible to catastrophes than younger ones [12,13]. Interestingly, tubulin PTMs are potential regulators of this process as much as, for long time, acetylated MTs were referred almost synonymously to old and stable MTs. Indeed, among its several biological functions [14], it has been shown that acetylation accumulates during MT aging and it has been proposed that the MT-acetylase α Tubulin Acetyl Transferase1 (αTAT1) can act as a clock for MT lifetimes [15], due to its preference for MTs and its low catalytic rate. Nevertheless, other candidates may be responsible for minor tubulin acetylation in vivo, including Elongator Complex Protein Elp3, which acts as tubulin acetylase, controlling the development and the migration of cortical neurons [16]. Furthermore, the age-dependent decrease of the activity of sirtuin 1, a widespread deacetylase which also acts on MTs, could lead to increased acetylation of α tubulin in the cerebellum of aged mice [17]. These data suggest a functional link between MT acetylation patterns and brain aging, evidencing how the regulation of MT stability is critical during normal neuronal aging and supporting the concept that its failure may be a reliable candidate in causing n...

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Tubulin acetylation: responsible enzymes, biological functions and human diseases

Cited by 222 publications

References 203 publications

M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

Expression of acetylated tubulin in the postnatal developing mouse cochlea

Is the Regulation of Microtubule Stability at the Crossroad Between Aging and Disease of Dopaminergic neurons?

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