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

Song, Yuyu; Brady, Scott T.

doi:10.1016/j.tcb.2014.10.004

Cited by 336 publications

(320 citation statements)

References 135 publications

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“…Acetylation is a reversible posttranslational modification that plays a fundamental role in the epigenetic regulation of gene expression 34. Interestingly, αTAT1 (also known as MEC‐17) is a specific acyltransferase that promotes α‐tubulin acetylation on lysine 40 (K40), and many studies have verified that elevated levels of acetylated α‐tubulin are a marker of stable microtubules 35, 36.…”

Section: Discussionmentioning

confidence: 99%

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Yang

Zhang

et al. 2018

JAHA

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BackgroundMany previous clinical studies have demonstrated that the nigrostriatal pathway, which plays a vital role in movement adjustment, is significantly impaired after stroke, according to medical imaging and autopsies. However, the basic pathomorphological changes have been poorly investigated to date. This study was designed to explore the pathomorphological changes, mechanism, and therapeutic method of nigrostriatal impairment after intracerebral hemorrhage (ICH).Methods and ResultsIntrastriatal injection of autologous blood or microtubule depolymerization reagent nocodazole was performed to mimic the pathology of ICH in C57/BL6 mice. Immunofluorescence, Western blotting, electron microscopy, functional behavioral tests, and anterograde and retrograde neural circuit tracking techniques were used in these mice. The data showed that the number of dopamine neurons and the dopamine concentration were severely decreased and that fine motor function was impaired after ICH. Microtubule depolymerization was the main contributor to the loss of dopamine neurons and to motor function deficits after ICH, as was also proven by intrastriatal injection of nocodazole. Moreover, administration of the microtubule stabilizer epothilone B (1.5 mg/kg) improved the integrity of the nigrostriatal pathway neural circuit, increased the number of dopamine neurons (4598±896 versus 3125±355; P=0.034) and the dopamine concentration (4.28±0.99 versus 3.08±0.75 ng/mg; P=0.041), and enhanced fine motor functional recovery associated with increased acetylated α‐tubulin expression to maintain microtubule stabilization after ICH.ConclusionsOur results clarified the pathomorphological changes of the nigrostriatal pathway after ICH and found that epothilone B helped alleviate nigrostriatal pathway injury after ICH, associated with promoting α‐tubulin acetylation to maintain microtubule stabilization, thus facilitating motor recovery.

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Section: Discussionmentioning

confidence: 99%

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Yang

Zhang

et al. 2018

JAHA

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“…In addition to specific microtubule-associated proteins, posttranslational modifications of tubulin are emerging as a significant mechanism that controls various microtubule functions, such as the recruitment of +TIPs and microtubule motors (Akhmanova and Steinmetz, 2008;Etienne-Manneville, 2013;Janke and Bulinski, 2011;Song and Brady, 2015). An interesting example is tubulin acetylation, a modification that is introduced by α-tubulin Nacetyltransferase 1 (ATAT1, hereafter referred to as αTAT1) and is removed by histone deacetylase 6 (HDAC6) (Song and Brady, 2015).…”

Section: Microtubule-associated Proteins In 3d Cell Migrationspecificmentioning

confidence: 99%

Microtubules in 3D cell motility

Bouchet

Akhmanova

2017

Journal of Cell Science

104

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Three-dimensional (3D) cell motility underlies essential processes, such as embryonic development, tissue repair and immune surveillance, and is involved in cancer progression. Although the cytoskeleton is a well-studied regulator of cell migration, most of what we know about its functions originates from studies conducted in twodimensional (2D) cultures. This research established that the microtubule network mediates polarized trafficking and signaling that are crucial for cell shape and movement in 2D. In parallel, developments in light microscopy and 3D cell culture systems progressively allowed to investigate cytoskeletal functions in more physiologically relevant settings. Interestingly, several studies have demonstrated that microtubule involvement in cell morphogenesis and motility can differ in 2D and 3D environments. In this Commentary, we discuss these differences and their relevance for the understanding the role of microtubules in cell migration in vivo. We also provide an overview of microtubule functions that were shown to control cell shape and motility in 3D matrices and discuss how they can be investigated further by using physiologically relevant models.

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“…Importantly, we show that ALC partially prevents METH-induced deacetylation, protecting the endothelial cells and consequently preserving the BBB function. Cytoskeleton microtubules are regulated by several types of conserved posttranslational modifications (Song and Brady, 2014). Although the biological meaning of such mechanisms is still poorly understood, it was reported that tubulin acetylation increases its stability and half-life, rendering microtubules more resistant to druginduced depolymerization and disassembly (Matsuyama et al, 2002;Szyk et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine promotes α-tubulin deacetylation in endothelial cells: The protective role of acetyl-l-carnitine

2015

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Methamphetamine (METH) is a powerful psychostimulant drug used worldwide for its reinforcing properties. In addition to the classic long-lasting monoaminergic-disrupting effects extensively described in the literature, METH has been consistently reported to increase blood brain barrier (BBB) permeability, both in vivo and in vitro, as a result of tight junction and cytoskeleton disarrangement. Microtubules play a critical role in cell stability, which relies on post-translational modifications such as a-tubulin acetylation. As there is evidence that psychostimulants drugs modulate the expression of histone deacetylases (HDACs), we hypothesized that in endothelial cells METH-mediation of cytoplasmatic HDAC6 activity could affect tubulin acetylation and further contribute to BBB dysfunction. To validate our hypothesis, we exposed the bEnd.3 endothelial cells to increasing doses of METH and verified that itleads to an extensivea-tubulin deacetylation mediated by HDACs activation. Furthermore, since we recently reported that acetyl-L-carnitine (ALC), a natural occurring compound, prevents BBB structural loss in a context of METH exposure, we reasoned that ALC could also preserve the acetylation of microtubules under METH action. The present results confirm that ALC is able to prevent METH-induced deacetylation providing effective protection on microtubule acetylation. Although further investigation is still needed, HDACs regulation may become a new therapeutic target for ALC.

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

Cited by 336 publications

References 135 publications

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Microtubules in 3D cell motility

Methamphetamine promotes α-tubulin deacetylation in endothelial cells: The protective role of acetyl-l-carnitine

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