HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions

Tran, Andy D.; Marmo, Timothy P.; Salam, Ambar A.; Che, Sally; Finkelstein, Erik I.; Kabarriti, Rafi; Xenias, Harry S.; Mazitschek, Ralph; Hubbert, Charlotte; Kawaguchi, Yoshiharu; Sheetz, Michael P.; Yao, Tso Pang; Bulinski, Chloe

doi:10.1242/jcs.03431

Cited by 245 publications

(232 citation statements)

References 79 publications

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“…Post-translational modifications of tubulin such as acetylation accumulate in stable microtubules 31 , however, it is unresolved as to whether acetylation actively stabilizes microtubules 30,[32][33][34][35][36] . As a measure of microtubule stability, we investigated their resistance to nocodazole, a microtubule depolymerizing drug.…”

Section: Resultsmentioning

confidence: 99%

αTAT1 is the major α-tubulin acetyltransferase in mice

et al. 2013

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Post-translational modification of tubulin serves as a powerful means for rapidly adjusting the functional diversity of microtubules. Acetylation of the e-amino group of K40 in a-tubulin is one such modification that is highly conserved in ciliated organisms. Recently, aTAT1, a Gcn5-related N-acetyltransferase, was identified as an a-tubulin acetyltransferase in Tetrahymena and C. elegans. Here we generate mice with a targeted deletion of Atat1 to determine its function in mammals. Remarkably, we observe a loss of detectable K40 a-tubulin acetylation in these mice across multiple tissues and in cellular structures such as cilia and axons where acetylation is normally enriched. Mice are viable and develop normally, however, the absence of Atat1 impacts upon sperm motility and male mouse fertility, and increases microtubule stability. Thus, aTAT1 has a conserved function as the major a-tubulin acetyltransferase in ciliated organisms and has an important role in regulating subcellular specialization of subsets of microtubules.

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Section: Resultsmentioning

confidence: 99%

αTAT1 is the major α-tubulin acetyltransferase in mice

et al. 2013

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“…Values are the average Ϯ SEM of at least 3 independent experiments; * P Ͻ 0.03; † P Ͻ 0.0001. peared independent of microtubule stability, 16,20,21 whereas in other studies including this one, increased acetylation induced increased microtubule stability. [13][14][15] The reasons for these conflicting results are not known but may reflect cell type differences in microtubule dynamics. Also, different assays were used to determine stability that likely vary in sensitivity and approach (for example, measuring nocodazole resistance versus real-time tubulin dynamics) such that conflicting results were obtained.…”

Section: Discussionmentioning

confidence: 99%

“…HDAC6 is the major tubulin deacetylase in liver and WIF-B cells (Grozinger et al 12 and manuscript in preparation), and when inhibited with TSA, increased microtubule acetylation and stability is observed. [13][14][15] We determined that 50 nM TSA for 30 minutes induced microtubule acetylation and stability to the same extent in WIF-B cells as did ethanol, allowing us to test our hypothesis. This result also suggested that acetylation induced microtubule stability, a topic that is currently controversial (for example, see Tran et al 15 and Palazzo et al 16 and the Discussion section).…”

mentioning

confidence: 93%

“…[13][14][15] We determined that 50 nM TSA for 30 minutes induced microtubule acetylation and stability to the same extent in WIF-B cells as did ethanol, allowing us to test our hypothesis. This result also suggested that acetylation induced microtubule stability, a topic that is currently controversial (for example, see Tran et al 15 and Palazzo et al 16 and the Discussion section). As shown in situ, [8][9][10] ethanol impaired albumin secretion and internalization of asialoglycoprotein receptor (ASGP-R), further confirming that WIF-B cells are a good model for studying alcoholic liver injury.…”

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confidence: 93%

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Microtubule acetylation and stability may explain alcohol-induced alterations in hepatic protein trafficking

et al. 2007

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We have been using polarized hepatic WIF-B cells to examine ethanol-induced liver injury. Previously, we determined microtubules were more highly acetylated and more stable in ethanol-treated WIF-B cells. We proposed that the ethanol-induced alterations in microtubule dynamics may explain the ethanol-induced defects in membrane trafficking that have been previously documented. To test this, we compared the trafficking of selected proteins in control cells and cells treated with ethanol or with the histone deacetylase 6 inhibitor trichostatin A (TSA). We determined that exposure to 50 nM TSA for 30 minutes induced microtubule acetylation (ϳ3-fold increase) and stability to the same extent as did ethanol. As shown previously in situ, the endocytic trafficking of the asialoglycoprotein receptor (ASGP-R) was impaired in ethanol-treated WIF-B cells. This impairment required ethanol metabolism and was likely mediated by acetaldehyde. TSA also impaired ASGP-R endocytic trafficking, but to a lesser extent. Similarly, both ethanol and TSA impaired transcytosis of the single-spanning apical resident aminopeptidase N (APN). For both ASGP-R and APN and for both treatments, the block in trafficking was internalization from the basolateral membrane. Interestingly, no changes in transcytosis of the glycophosphatidylinositol-anchored protein, 5 -nucleotidase, were observed, suggesting that increased microtubule acetylation and stability differentially regulate internalization. We further determined that albumin secretion was impaired in both ethanol-treated and TSA-treated cells, indicating that increased microtubule acetylation and stability also disrupted this transport step. Conclusion: These results indicate that altered microtubule dynamics explain in part alcoholinduced defects in membrane trafficking. (HEPATOLOGY 2008;47:1745-1753 A lcoholic liver disease is a major biomedical health concern in the United States. Although the progression of this disease has been well described clinically, little is known about the molecular basis for liver injury. Research aimed at identifying the molecules and pathways that promote alcohol-induced hepatotoxicity has been hampered by the lack of good in vitro models. Our recent studies have been performed in WIF-B cells, an emerging model system for the study of alcohol-induced liver injury. These hepatic cells are highly differentiated and form discrete apical and basolateral membrane domains in culture. Domain-specific membrane proteins are localized in WIF-B cells as they are in hepatocytes in situ, and many liver-specific functions are maintained. 1 Importantly, WIF-B cells metabolize ethanol using alcohol dehydrogenase (ADH) and cytochrome P4502E 1 . 2 Like hepatocytes, ethanol-treated WIF-B cells display a reduced redox state and increased triglycerides. 2 More recently, we discovered that microtubule repolymerization was impaired in ethanol-treated WIF-B cells, 3 consistent with reports performed in vitro and in isolated hepatocytes. [4][5][6] We also found that steady-state micro...

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“…13,14 Hyperacetylated microtubules decreased microtubule dynamics, increased microtubule stability and decreased cell migration. 15 Therefore, tubulin acetylation/deacetylation is implicated in the control of microtubule function and, therefore, the regulatory mechanism of tubulin acetylation/deacetylation by acetylase/deacetylase has attracted much attention.…”

Section: Sirt2 and Endothelial Microtubule Reorganization A Hashimotomentioning

confidence: 99%

Angiotensin II induces microtubule reorganization mediated by a deacetylase SIRT2 in endothelial cells

et al. 2011

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Angiotensin II has been implicated in vascular remodeling. Microtubule composed of tubulins regulates cell shape, migration and survival. Tubulin acetylation has an important role in the control of microtubule structure and microtubule-based cellular functions. In this study, angiotensin II induced disassembly and deacetylation of a-tubulin, which were blocked by pretreatment with an angiotensin II type 1 receptor blocker losartan and a sirtuin class deacetylase inhibitor sirtinol, and by depletion of a deacetylase SIRT2 using RNA interference. We investigated the involvement of SIRT2 in angiotensin II-induced endothelial cell migration using the Boyden chamber method. Angiotensin II caused a significant increase in cell migration, which was blocked by pretreatment with sirtinol and SIRT2 depletion. It has been reported that angiotensin II is involved in cytoskeletal reorganization stimulated by mechanical stretch in endothelial cells. We also demonstrated that endothelial cells subjected to a 10% uniaxial stretch showed vertical alignment to the direction of tension and tubulin deacetylation in the peripheral side of cells, in comparison with control static cells. The mechanical stretch-induced changes of microtubules were blocked by pretreatment with sirtinol and SIRT2 depletion. Immunofluorescence microscopy showed that acetylated tubulin was decreased in platelet-endothelial cell adhesion molecule-1-positive cells in the intima of the aortic walls in mice loaded with angiotensin II, in comparison with mice loaded with control vehicle. These data show that angiotensin II and mechanical stretch stimulate microtubule redistribution and deacetylation via SIRT2 in endothelial cells, suggesting the emerging role of SIRT2 in hypertension-induced vascular remodeling.

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HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions

Cited by 245 publications

References 79 publications

αTAT1 is the major α-tubulin acetyltransferase in mice

αTAT1 is the major α-tubulin acetyltransferase in mice

Microtubule acetylation and stability may explain alcohol-induced alterations in hepatic protein trafficking

Angiotensin II induces microtubule reorganization mediated by a deacetylase SIRT2 in endothelial cells

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