scholarly journals Loss of Deacetylation Enzymes Hdac6 and Sirt2 Promotes Acetylation of Cytoplasmic Tubulin, but Suppresses Axonemal Acetylation in Zebrafish Cilia

2021 ◽  
Vol 9 ◽  
Author(s):  
Paweł K. Łysyganicz ◽  
Niedharsan Pooranachandran ◽  
Xinming Liu ◽  
Kathryn I. Adamson ◽  
Katarzyna Zielonka ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Primary Cilia ◽  
Extracellular Fluid ◽  
Histone Acetyltransferases ◽  
Compensatory Mechanism ◽  
Post Translational Modification ◽  
Zebrafish Model ◽  
Alpha Tubulin ◽  
Tubulin Acetylation ◽  
Sensory Cilia

Cilia are evolutionarily highly conserved organelles with important functions in many organs. The extracellular component of the cilium protruding from the plasma membrane comprises an axoneme composed of microtubule doublets, arranged in a 9 + 0 conformation in primary cilia or 9 + 2 in motile cilia. These microtubules facilitate transport of intraflagellar cargoes along the axoneme. They also provide structural stability to the cilium, which may play an important role in sensory cilia, where signals are received from the movement of extracellular fluid. Post-translational modification of microtubules in cilia is a well-studied phenomenon, and acetylation on lysine 40 (K40) of alpha tubulin is prominent in cilia. It is believed that this modification contributes to the stabilization of cilia. Two classes of enzymes, histone acetyltransferases and histone deacetylases, mediate regulation of tubulin acetylation. Here we use a genetic approach, immunocytochemistry and behavioral tests to investigate the function of tubulin deacetylases in cilia in a zebrafish model. By mutating three histone deacetylase genes (Sirt2, Hdac6, and Hdac10), we identify an unforeseen role for Hdac6 and Sirt2 in cilia. As expected, mutation of these genes leads to increased acetylation of cytoplasmic tubulin, however, surprisingly it caused decreased tubulin acetylation in cilia in the developing eye, ear, brain and kidney. Cilia in the ear and eye showed elevated levels of mono-glycylated tubulin suggesting a compensatory mechanism. These changes did not affect the length or morphology of cilia, however, functional defects in balance was observed, suggesting that the level of tubulin acetylation may affect function of the cilium.

scholarly journals Bromodomains as therapeutic targets

2011 ◽  
Vol 13 ◽  
Author(s):  
Susanne Muller ◽  
Panagis Filippakopoulos ◽  
Stefan Knapp
Keyword(s):  
Squamous Cell Carcinoma ◽  
Drug Development ◽  
Cell Carcinoma ◽  
Protein Interaction ◽  
Histone Deacetylases ◽  
Histone Acetyltransferases ◽  
Reading Process ◽  
Post Translational Modification ◽  
Disease Biology ◽  
Lysine Residues

Acetylation of lysine residues is a post-translational modification with broad relevance to cellular signalling and disease biology. Enzymes that ‘write’ (histone acetyltransferases, HATs) and ‘erase’ (histone deacetylases, HDACs) acetylation sites are an area of extensive research in current drug development, but very few potent inhibitors that modulate the ‘reading process’ mediated by acetyl lysines have been described. The principal readers of ɛ-N-acetyl lysine (Kac) marks are bromodomains (BRDs), which are a diverse family of evolutionary conserved protein-interaction modules. The conserved BRD fold contains a deep, largely hydrophobic acetyl lysine binding site, which represents an attractive pocket for the development of small, pharmaceutically active molecules. Proteins that contain BRDs have been implicated in the development of a large variety of diseases. Recently, two highly potent and selective inhibitors that target BRDs of the BET (bromodomains and extra-terminal) family provided compelling data supporting targeting of these BRDs in inflammation and in an aggressive type of squamous cell carcinoma. It is likely that BRDs will emerge alongside HATs and HDACs as interesting targets for drug development for the large number of diseases that are caused by aberrant acetylation of lysine residues.

Increased microtubule stability and alpha tubulin acetylation in cells transfected with microtubule-associated proteins MAP1B, MAP2 or tau

1992 ◽  
Vol 103 (4) ◽  
pp. 953-964 ◽  
Author(s):  
R. Takemura ◽  
S. Okabe ◽  
T. Umeyama ◽  
Y. Kanai ◽  
N.J. Cowan ◽  
...  
Keyword(s):  
Post Translational Modification ◽  
3T3 Cells ◽  
Microtubule Organization ◽  
Alpha Tubulin ◽  
Transfected Cells ◽  
Microtubule Associated Proteins ◽  
Cos Cells ◽  
Tubulin Acetylation ◽  
Microtubule Stability ◽  
Associated Proteins

We previously transfected MAP2, tau and MAP1B cDNA into fibroblasts and have studied the effect of expression of these microtubule-associated proteins on microtubule organization. In this study, we examined some additional characteristics of microtubule bundles and arrays formed in fibroblasts transfected with these microtubule-associated proteins. It was found that microtubule bundles formed in MAP2c- or tau-transfected cells were stabilized against microtubule depolymerizing reagents and were enriched in acetylated alpha tubulin. When mouse MAP1B cDNA was expressed following transfection into COS cells, MAP1B was localized along microtubule arrays, but no extensive reorganization of microtubules such as bundle formation was observed, in agreement with our previous finding using HeLa and 3T3 cells. However, stabilization of microtubules was indicated: (a) microtubules in MAP1B-transfected cells were stabilized against a microtubule depolymerizing reagent, although stabilization was less efficient than that seen in MAP2c- or tau-transfected cells, and (b) microtubules in MAP1B-transfected cells were enriched in acetylated alpha tubulin. These results suggest that neuronal microtubule-associated proteins introduced into fibroblasts by cDNA transfection stabilize microtubules and affect the state of post-translational modification of tubulin.

Flagellar regeneration of the trypanosome Crithidia fasciculata involves post-translational modification of cytoplasmic alpha tubulin

1984 ◽  
Vol 4 (6) ◽  
pp. 1182-1185
Author(s):  
D G Russell ◽  
K Gull
Keyword(s):  
Post Translational Modification ◽  
Crithidia Fasciculata ◽  
Alpha Tubulin ◽  
Rna Translation ◽  
Polyadenylated Rna ◽  
Flagellar Regeneration

Deflagellation of Crithidia fasciculata stimulated formation of new flagella and maximized production of alpha 3 tubulin. Continuous labeling during reflagellation revealed that alpha 1, 2, and 3 tubulins were formed, whereas the polyadenylated RNA translation products lacked alpha 3 isoform. Pulse-chase labeling experiments demonstrated that alpha 3 was a post-translational modification of cytoplasmic alpha tubulin.

scholarly journals Tubulin heterogeneity in the trypanosome Crithidia fasciculata.

1984 ◽  
Vol 4 (4) ◽  
pp. 779-790 ◽  
Author(s):  
D G Russell ◽  
D Miller ◽  
K Gull
Keyword(s):  
Gel Electrophoresis ◽  
Peptide Mapping ◽  
Polyacrylamide Gel Electrophoresis ◽  
Polyacrylamide Gel ◽  
In Vitro Translation ◽  
Two Dimensional ◽  
Post Translational Modification ◽  
Interphase Cell ◽  
Crithidia Fasciculata ◽  
Alpha Tubulin

The interphase cell of Crithidia fasciculata has three discrete tubulin populations: the subpellicular microtubules, the axonemal microtubules, and the nonpolymerized cytoplasmic pool protein. These three tubulin populations were independently and selectively purified, yielding, in each case, microtubule protein capable of self-assembly. All three preparations polymerized to form ribbons and sheets rather than the more usual microtubular structures. Analyses of the tubulin by two-dimensional polyacrylamide gel electrophoresis, isoelectric focusing, and peptide mapping indicated that the beta-tubulin complex remained constant regardless of source but that some heterogeneity was present in the alpha subunit. Cytoplasmic pool alpha tubulins (alpha 1/alpha 2) were the only alpha isotypes in the cytoplasm and also formed most of the alpha tubulin species in the pellicular fraction. Flagellar alpha tubulin (alpha 3) was the sole alpha isotype in the flagella; it appeared in small amounts in the pellicular fraction but was completely absent from the cytoplasm. In vitro translation products from polyadenylated RNA from C. fasciculata were also examined by two-dimensional polyacrylamide gel electrophoresis and possessed a protein corresponding to alpha 1/alpha 2 tubulin but lacked any alpha 3 tubulin. The alpha 3 polypeptide arose from a post-translational modification of a precursor polypeptide not identifiable by two-dimensional polyacrylamide gel electrophoresis as alpha 3. Peptide mapping data indicated that cytoplasmic alpha tubulin is the most likely precursor. These results demonstrate alpha-tubulin heterogeneity in this organism and also how close the relationship between flagellar and cytoskeletal tubulins can be among lower eucaryotes.

The axonemal microtubules of the Chlamydomonas flagellum differ in tubulin isoform content

1998 ◽  
Vol 111 (3) ◽  
pp. 313-320 ◽  
Author(s):  
K.A. Johnson
Keyword(s):  
Structure And Function ◽  
Post Translational Modification ◽  
Immunofluorescence Analysis ◽  
Central Pair ◽  
Alpha Tubulin ◽  
Microtubule Polymerization ◽  
Tubulin Isoforms ◽  
Flagellar Assembly ◽  
Tyrosinated Tubulin ◽  
And Function

Little is known of the molecular basis for the diversity of microtubule structure and function found within the eukaryotic flagellum. Antibodies that discriminate between tyrosinated alpha tubulin and post-translationally detyrosinated alpha tubulin were used to localize these complementary tubulin isoforms in flagella of the single-celled green alga Chlamydomonas reinhardtii. Immunofluorescence analysis of intact axonemes detected both isoforms along most of the lengths of flagella; however, each had a short distal zone rich in tyrosinated tubulin. Localizations on splayed axonemes revealed that the microtubules of the central-pair apparatus were rich in tyrosinated tubulin, while outer doublets contained a mixture of both isoforms. Immunoelectron analysis of individual outer doublets revealed that while tyrosinated tubulin was present in both A and B tubules, detyrosinated tubulin was largely confined to the wall of the B hemi-tubules. The absence of detyrosinated tubulin from the A tubules of the outer doublets and the microtubules of the central pair, both of which extend past the B hemi-tubules of the outer doublets in the flagellar tip, explained the appearance of a tyrosinated tubulin-rich distal zone on intact axonemes. Localizations performed on cells regenerating flagella revealed that flagellar assembly used tyrosinated tubulin; detyrosination of the B tubule occurred during later stages of regeneration, well after microtubule polymerization. The developmental timing of detyrosination, which occurs over a period during which the regrowing flagella begin to beat more effectively, suggests that post-translational modification of the B tubule surface may enhance dynein/B tubule interactions that power flagellar beating.

scholarly journals The Histone Deacetylases HosA and HdaA Affect the Phenotype and Transcriptomic and Metabolic Profiles of Aspergillus niger

Toxins ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 520 ◽  
Author(s):  
Xuejie Li ◽  
Lijie Pan ◽  
Bin Wang ◽  
Li Pan
Keyword(s):  
Metabolic Pathways ◽  
Histone Deacetylases ◽  
Chromatin Accessibility ◽  
Growth Stress ◽  
Pigment Production ◽  
Histone Acetyltransferases ◽  
Metabolic Profiles ◽  
Phenotypic Analysis ◽  
Histone Modifying Enzymes ◽  
New Strategies

Histone acetylation is an important modification for the regulation of chromatin accessibility and is controlled by two kinds of histone-modifying enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). In filamentous fungi, there is increasing evidence that HATs and HDACs are critical factors related to mycelial growth, stress response, pathogenicity and production of secondary metabolites (SMs). In this study, seven A. niger histone deacetylase-deficient strains were constructed to investigate their effects on the strain growth phenotype as well as the transcriptomic and metabolic profiles of secondary metabolic pathways. Phenotypic analysis showed that deletion of hosA in A. niger FGSC A1279 leads to a significant reduction in growth, pigment production, sporulation and stress resistance, and deletion of hdaA leads to an increase in pigment production in liquid CD medium. According to the metabolomic analysis, the production of the well-known secondary metabolite fumonisin was reduced in both the hosA and hdaA mutants, and the production of kojic acid was reduced in the hdaA mutant and slightly increased in the hosA mutant. Results suggested that the histone deacetylases HosA and HdaA play a role in development and SM biosynthesis in A. niger FGSC A1279. Histone deacetylases offer new strategies for regulation of SM synthesis.

scholarly journals Histone Deacetylation Inhibitors as Therapy Concept in Sepsis

2019 ◽  
Vol 20 (2) ◽  
pp. 346 ◽  
Author(s):  
Andreas von Knethen ◽  
Bernhard Brüne
Keyword(s):  
Organ Failure ◽  
Expression Profile ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Histone Deacetylation ◽  
Histone Acetyltransferases ◽  
Open Chromatin ◽  
Nucleosome Structure ◽  
Active Transcription ◽  
Anti Inflammatory

Sepsis is characterized by dysregulated gene expression, provoking a hyper-inflammatory response occurring in parallel to a hypo-inflammatory reaction. This is often associated with multi-organ failure, leading to the patient’s death. Therefore, reprogramming of these pro- and anti-inflammatory, as well as immune-response genes which are involved in acute systemic inflammation, is a therapy approach to prevent organ failure and to improve sepsis outcomes. Considering epigenetic, i.e., reversible, modifications of chromatin, not altering the DNA sequence as one tool to adapt the expression profile, inhibition of factors mediating these changes is important. Acetylation of histones by histone acetyltransferases (HATs) and initiating an open-chromatin structure leading to its active transcription is counteracted by histone deacetylases (HDACs). Histone deacetylation triggers a compact nucleosome structure preventing active transcription. Hence, inhibiting the activity of HDACs by specific inhibitors can be used to restore the expression profile of the cells. It can be assumed that HDAC inhibitors will reduce the expression of pro-, as well as anti-inflammatory mediators, which blocks sepsis progression. However, decreased cytokine expression might also be unfavorable, because it can be associated with decreased bacterial clearance.

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