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Effect of SIRT2 on the TPPP/p25-induced tubulin polymerization. (a) Tubulin polymerization (6 μM) promoted by TPPP/p25 (3 μM) in the absence and presence of inactive or active (with 500 μM NAD + ) SIRT2 (25 μM). The tubulin polymerization was induced by the addition of TPPP/p25 or TPPP/p25 preincubated with SIRT2. (b) Electron microscopic images of the pellet fractions produced by TPPP/p25induced tubulin assembly in absence and presence of SIRT2 (with NAD + ) (a). (c) and (d) Western blot images of supernatant (S) and pellet (P) fractions using acetyl-tubulin antibody, when polymerization was induced by TPPP/p25 premixed with SIRT2 (c) or SIRT2 was added to the TPPP/p25-assembled tubulin (d). All data of the representative experiments can be found in the source data file. The images of the full-length blots are presented in Supplementary Figs S2 and S3.
Source publication
The microtubule network exerts multifarious functions controlled by its decoration with various proteins and post-translational modifications. The disordered microtubule associated Tubulin Polymerization Promoting Protein (TPPP/p25) and the NAD⁺-dependent tubulin deacetylase sirtuin-2 (SIRT2) play key roles in oligodendrocyte differentiation by act...
Contexts in source publication
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... of SIRT2 with TPPP/p25 and/or tubulin, the functional consequences of the heterologous associations were char- acterized: on one hand, the role of SIRT2 in the TPPP/p25-promoted tubulin assembly; on the other hand, the role of TPPP/p25 in the SIRT2-derived tubulin deacetylation. The following types of experiments were performed as illustrated in Fig. 4: i) TPPP/p25-induced tubulin polymerization as detected by turbidimetry; ii) determina- tion of the partition of proteins in the supernatant and pellet fractions of the samples obtained in the tubulin polymerization assay; iii) quantification of the tubulin acetylation degree by Western blot; iv) visualization of the assembled tubulin ...
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... shown in Fig. 4, SIRT2 decreases the tubulin polymerization activity of TPPP/p25, when they were premixed, as indicated by the reduced turbidity level; the effect appears to be independent of the presence of NAD + (Fig. 4a). When the same set of experiments was performed, however, SIRT2 was added to the TPPP/ p25-assembled tubulin (control curve at 6 ...
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... shown in Fig. 4, SIRT2 decreases the tubulin polymerization activity of TPPP/p25, when they were premixed, as indicated by the reduced turbidity level; the effect appears to be independent of the presence of NAD + (Fig. 4a). When the same set of experiments was performed, however, SIRT2 was added to the TPPP/ p25-assembled tubulin (control curve at 6 min in Fig. 4a), there was no significant decrease in the turbidity (Supplementary Table S2). This finding indicates the resistance of the TPPP/p25-assembled MT ultrastructures against the destructive effect ...
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... 4, SIRT2 decreases the tubulin polymerization activity of TPPP/p25, when they were premixed, as indicated by the reduced turbidity level; the effect appears to be independent of the presence of NAD + (Fig. 4a). When the same set of experiments was performed, however, SIRT2 was added to the TPPP/ p25-assembled tubulin (control curve at 6 min in Fig. 4a), there was no significant decrease in the turbidity (Supplementary Table S2). This finding indicates the resistance of the TPPP/p25-assembled MT ultrastructures against the destructive effect of SIRT2. The ultrastructures formed by the TPPP/p25-promoted tubulin polym- erization were visualized by electron microscopy in the presence of ...
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... decrease in the turbidity (Supplementary Table S2). This finding indicates the resistance of the TPPP/p25-assembled MT ultrastructures against the destructive effect of SIRT2. The ultrastructures formed by the TPPP/p25-promoted tubulin polym- erization were visualized by electron microscopy in the presence of either active or inactive SIRT2 (Fig. 4b). The results of this set of experiments unambiguously show that SIRT2, when it was premixed with TPPP/p25, coun- teracts the TPPP/p25-induced tubulin polymerization independently of its catalytic ...
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... study the effect of TPPP/p25 on the SIRT2-derived tubulin deacetylation, the deacetylase activity of SIRT2 was measured on acetyl-tubulin, and quantified by Western blot using specific acetyl-tubulin antibody. Figure 5 and Supplementary Fig. S4 show that SIRT2 decreased the acetylation level of tubulin in a concentration-dependent manner. At a given SIRT2 concen- tration (1.5 µM), increasing TPPP/p25 concentrations provoked an increase in the tubulin acetylation level sug- gesting a reduced deacetylation activity of SIRT2 due to its interaction with TPPP/p25. ...
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... data are presented as mean ± SD, n = 3 for the SIRT2 concentration serie, and n = 4 for the TPPP/p25 concentration serie at 1.5 μM SIRT2 concentration. Images of the full-length blots/gels are presented in Supplementary Fig. S4. ...
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... HDAC6 16 and SIRT2 29 ; however, the functional consequences of the interaction of TPPP/p25 with SIRT2 have not been elucidated. Here we have shown that SIRT2 reduces the TPPP/p25-induced tubulin assembly in vitro, it counteracts the tubulin polymerization pro- moting/MT bundling potency of TPPP/p25 independently of its deacetylase activity (cf . Fig. 4); however, this effect does not occur when SIRT2 is added to the TPPP/p25-assembled tubulin (no turbidity change) (cf. Fig. 4 and Supplementary Figs S2 and S3). Furthermore, the TPPP/p25-promoted ultrastructures, which show resist- ance against deacetylation, are not accessible for SIRT2 (cf. Fig. 4 and Supplementary Figs S2 and ...
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... Here we have shown that SIRT2 reduces the TPPP/p25-induced tubulin assembly in vitro, it counteracts the tubulin polymerization pro- moting/MT bundling potency of TPPP/p25 independently of its deacetylase activity (cf . Fig. 4); however, this effect does not occur when SIRT2 is added to the TPPP/p25-assembled tubulin (no turbidity change) (cf. Fig. 4 and Supplementary Figs S2 and S3). Furthermore, the TPPP/p25-promoted ultrastructures, which show resist- ance against deacetylation, are not accessible for SIRT2 (cf. Fig. 4 and Supplementary Figs S2 and ...
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... independently of its deacetylase activity (cf . Fig. 4); however, this effect does not occur when SIRT2 is added to the TPPP/p25-assembled tubulin (no turbidity change) (cf. Fig. 4 and Supplementary Figs S2 and S3). Furthermore, the TPPP/p25-promoted ultrastructures, which show resist- ance against deacetylation, are not accessible for SIRT2 (cf. Fig. 4 and Supplementary Figs S2 and ...
Citations
... In physiological conditions, TPPP modulates the dynamics and stability of the cytoskeletal microtubule system via its bundling and tubulin acetylation-promoting activities [13]. These physiological functions are mediated by its direct associations with tubulin/microtubules as well as with tubulin deacetylases such as histone deacetylase 6 and sirtuin-2 (SIRT2) [20,21]. The bundling and stabilization of microtubules result from the dimerization of the tubulinattached monomeric TPPP [22]. ...
Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities such as the regulation of the microtubule network and the promotion of SYN aggregation. The role of TPPP in Parkinsonism is often neglected in research, which we here attempt to remedy. In the normal brain, SYN and TPPP are expressed endogenously in neurons and oligodendrocytes, respectively, whilst, at an early stage of Parkinsonism, soluble hetero-associations of these proteins are found in both cell types. The cell-to-cell transmission of these proteins, which is central to disease progression, provides a unique situation for specific drug targeting. Different strategies for intervention and for the discovery of biomarkers include (i) interface targeting of the SYN-TPPP hetero-complex; (ii) proteolytic degradation of SYN and/or TPPP using the PROTAC technology; and (iii) depletion of the proteins by miRNA technology. We also discuss the potential roles of SYN and TPPP in the phenotype stabilization of neurons and oligodendrocytes.
... Previously, we showed that TPPP1 regulates the dynamics and stability of the microtubule network through its acetylation-enhancing activity by inhibiting the cytosolic tubulin deacetylase enzymes, histone deacetylase 6 and sirtuin-2 [43,55]. We tested the effect of TPPP3, as compared to that of TPPP1, on the microtubule acetylation by Western blot in HeLa cells expressing TPPP3 and TPPP1, as described in the Materials and Methods Section. ...
Parkinson’s disease is characterized by locomotion deficits, dopaminergic neuronal loss and alpha-synuclein (SYN) aggregates; the Tubulin Polymerization Promoting Protein (TPPP/p25 or TPPP1) is also implicated in these processes. The moonlighting and chameleon TPPP1 modulates the dynamics/stability of the multifunctional microtubule network by promoting its acetylation and bundling. Previously, we identified the microtubule-associated TPPP3, a homologue of TPPP1 lacking its N-terminus; however, its involvement in physiological or pathological processes was not elucidated. In this work, we have shown the modulatory role of TPPP3, similarly to TPPP1, in microtubule organization, as well as its homo- and hetero-associations with TPPP1. TPPP3, in contrast to TPPP1, virtually does not bind to SYN; consequently, it does not promote SYN aggregation. Its anti-aggregative potency is achieved by counteracting the formation of the TPPP1–SYN pathological complex/aggregation leading to Parkinsonism. The interactions of TPPP3 have been determined and quantified in vitro with recombinant human proteins, cell extracts and in living human cells using different methods including bifunctional fluorescence complementation. The tight association of TPPP3 with TPPP1, but not with SYN, may ensure a unique mechanism for its inhibitory effect. TPPP3 or its selected fragments may become a leading agent for developing anti-Parkinson agents.
... Interestingly, APE treatment induced a significant upregulation of SIRT2 expression 30 h after treatment, in line with the increased accumulation of the cells in the M phase. Moreover, SIRT2 activity may contribute to the formation of deacetylated unstable microtubules [37]. In our experiments, we observed a decrease in acetylated tubulin expression, particularly in the U87 cells. ...
Background:
Glioblastoma multiforme (GBM) is characterized by several genetic abnormalities, leading to cell cycle deregulation and abnormal mitosis caused by a defective checkpoint. We previously demonstrated that arecaidine propargyl ester (APE), an orthosteric agonist of M2 muscarinic acetylcholine receptors (mAChRs), arrests the cell cycle of glioblastoma (GB) cells, reducing their survival. The aim of this work was to better characterize the molecular mechanisms responsible for this cell cycle arrest.
Methods:
The arrest of cell proliferation was evaluated by flow cytometry analysis. Using immunocytochemistry and time-lapse analysis, the percentage of abnormal mitosis and aberrant mitotic spindles were assessed in both cell lines. Western blot analysis was used to evaluate the modulation of Sirtuin2 and acetylated tubulin-factors involved in the control of cell cycle progression.
Results:
APE treatment caused arrest in the M phase, as indicated by the increase in p-HH3 (ser10)-positive cells. By immunocytochemistry, we found a significant increase in abnormal mitoses and multipolar mitotic spindle formation after APE treatment. Time-lapse analysis confirmed that the APE-treated GB cells were unable to correctly complete the mitosis. The modulated expression of SIRT2 and acetylated tubulin in APE-treated cells provides new insights into the mechanisms of altered mitotic progression in both GB cell lines.
Conclusions:
Our data show that the M2 agonist increases aberrant mitosis in GB cell lines. These results strengthen the idea of considering M2 acetylcholine receptors a novel promising therapeutic target for the glioblastoma treatment.
... TPPP increases acetyla-tubulin level through binding and inhibiting HDAC6 in microtubules [15]. TPPP counteracts the SIRT2-dependent a-tubulin deacetylation [25]. Thus, induction of TPPP and change of its subcellular distribution may be important events for the final stage of differentiation in OLGs. ...
SIRT1 is involved in the regulation of a variety of biological processes such as metabolism, stress response, autophagy and differentiation. Although progenitor cells of oligodendrocytes (OPCs) express high level of SIRT1, its function on differentiation is unknown. Because we have shown that SIRT1 plays a pivotal role in differentiation of neural precursor cells, we hypothesized that SIRT1 may also participate in the differentiation of oligodendrocytes (OLGs). We examined whether SIRT1 was expressed in two human oligodendrocyte cell lines: KG-1-C and MO 3.13 OLG. Transfection of cell lines with SIRT1-siRNA and SIRT2-siRNA promoted the extension of cellular processes. SIRT1-siRNA and SIRT2-siRNA increased acetyl-α-tubulin level, conversely, over expression of SIRTs resulted in decreased the ratio of acetyl-α-tubulin to α-tubulin. We also found knockdown of SIRT1 and SIRT2 induced overexpression of βIV-tubulin and tubulin polymerization promoting protein (TPPP) (OLG-specific cytoskeleton-related molecules) that distributed widely in cell bodies. Taken together, SIRT1 may play a role in oligodenroglial differentiation and myelinogenesis.
... 165,166 In addition, the enzyme shares a number of non-histone substrates with SIRT1, such as FOXO1, FOXO3, and p53, [167][168][169] which modulate cell cycle progression and apoptosis, as well as, uniquely, a-tubulin, which contributes to oligodendrocyte differentiation. 170 In terms of carcinogenic functionality, SIRT2 has demonstrated roles both in tumor development as well as suppression. Murine SIRT2 deficiency leads to a robust tumorigenic response, 171 and human melanomas and gliomas have been found to be associated with various abnormalities and expression changes in the SIRT2 locus, 172,173 indicating the enzyme's tumor-suppressive capability. ...
NAD ⁺ and its derivatives NADH, NADP ⁺ , and NADPH are essential cofactors in redox reactions and electron transport pathways. NAD serves also as substrate for an extensive series of regulatory enzymes including cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases which are O-acetyl-ADP-ribosyltransferases. As a result of the numerous and diverse enzymes that utilize NAD as well as depend on its synthesis and concentration, significant interest has developed in its role in a variety of physiologic and pathologic processes, and therapeutic initiatives have focused both on augmenting its levels as well as inhibiting some of its pathways. In this article, we examine the biosynthesis of NAD, metabolic processes in which it is involved, and its role in aging, cancer, and other age-associated comorbidities including neurodegenerative, cardiovascular, and metabolic disorders. Therapeutic interventions to augment and/or inhibit these processes are also discussed.
Impact statement
NAD is a central metabolite connecting energy balance and organismal growth with genomic integrity and function. It is involved in the development of malignancy and has a regulatory role in the aging process. These processes are mediated by a diverse series of enzymes whose common focus is either NAD’s biosynthesis or its utilization as a redox cofactor or enzyme substrate. These enzymes include dehydrogenases, cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases. This article describes the manifold pathways that comprise NAD metabolism and promotes an increased awareness of how perturbations in these systems may be important in disease prevention and/or progression.
... SIRT2 is abundant in neurons, its level is relatively high in OLGs, the major constituent of the myelin sheath [60][61][62][63]. The inhibition of SIRT2 by TPPP/p25 manifests itself within the SIRT2-tubulin-TPPP/p25 ternary complex, the concentrationdependent formation of which was quantified by experimental-based mathematical modelling [64]. Co-localization of the SIRT2-TPPP/p25 complex with the microtubule network was visualized in HeLa cells by immunofluorescence microscopy using Bimolecular Fluorescence Complementation technology [64] (Figure 5). ...
... The inhibition of SIRT2 by TPPP/p25 manifests itself within the SIRT2-tubulin-TPPP/p25 ternary complex, the concentrationdependent formation of which was quantified by experimental-based mathematical modelling [64]. Co-localization of the SIRT2-TPPP/p25 complex with the microtubule network was visualized in HeLa cells by immunofluorescence microscopy using Bimolecular Fluorescence Complementation technology [64] (Figure 5). However, the TPPP/p25-associated microtubule ultrastructures appeared to be resistant against SIRT2 activity due to the inaccessibility of the acetylated Lys40 residue. ...
... However, the TPPP/p25-associated microtubule ultrastructures appeared to be resistant against SIRT2 activity due to the inaccessibility of the acetylated Lys40 residue. It has been proposed that the structural and functional effects of TPPP/p25 on the tubulin deacetylase SIRT2 could provide the fine-tuning of the regulation of microtubule dynamics and stability [64]. SIRT2 silencing by siRNA was reported to increase tubulin acetylation and the complexity of cellular arborization in OLGs, while its over-expression displayed opposite effects [65,66]. ...
The sensing, integrating, and coordinating features of the eukaryotic cells are achieved by the complex ultrastructural arrays and multifarious functions of the cytoskeleton, including the microtubule network. Microtubules play crucial roles achieved by their decoration with proteins/enzymes as well as by posttranslational modifications. This review focuses on the Tubulin Polymerization Promoting Protein (TPPP/p25), a new microtubule associated protein, on its “regulatory functions by day and pathological functions at night”. Physiologically, the moonlighting TPPP/p25 modulates the dynamics and stability of the microtubule network by bundling microtubules and enhancing the tubulin acetylation due to the inhibition of tubulin deacetylases. The optimal endogenous TPPP/p25 level is crucial for its physiological functions, to the differentiation of oligodendrocytes, which are the major constituents of the myelin sheath. Pathologically, TPPP/p25 forms toxic oligomers/aggregates with α-synuclein in neurons and oligodendrocytes in Parkinson’s disease and Multiple System Atrophy, respectively; and their complex is a potential therapeutic drug target. TPPP/p25-derived microtubule hyperacetylation counteracts uncontrolled cell division. All these issues reveal the anti-mitotic and α-synuclein aggregation-promoting potency of TPPP/p25, consistent with the finding that Parkinson’s disease patients have reduced risk for certain cancers.
... HDAC6 is ubiquitously expressed and localized primarily in the cytoplasm [10], and it is considered as the major tubulin deacetylase ([11] and references therein). The brain-specific Tubulin Polymerization Promoting Protein (TPPP/p25) as a MAP regulates the dynamics and stability of the MT network via its tubulin polymerization promoting, MT bundling and tubulin acetylation enhancing activities [12][13][14][15]. The direct interaction of TPPP/p25 with HDAC6 results in the inhibition of the deacetylase activity of the enzyme, thus the hyperacetylation of the tubulin/MT network [13,16]. ...
... Fig. 3C and D show the partition of the proteins in the supernatant and pellet fractions. TPPP/p25 can be detected mainly in the pellet fraction, when it was incubated with tubulin/MTs, in agreement with our previous results [15,18]. Significant amount of LC8-2 could also be detected in the pellet only in the presence of TPPP/p25 (when all three proteins were present), indicating a crucial role of TPPP/p25 in promoting the binding of LC8-2 to the tubulin-containing fractions. ...
... In order to validate the in vitro data at cellular level, immunofluorescence microscopy coupled with BiFC assays were applied for the visualization of the direct association of LC8-2 with TPPP/p25 and HDAC6 in living HeLa cells. The same method was used previously for the visualization of the intracellular binding of TPPP/p25 to sirtuin-2 and α-synuclein [15,46]. Venus fusion constructs of LC8-2 and TPPP/ p25 as well as that of LC8-2 and HDAC6 were produced by recombinant technology, and the heteroassociations were visualized by fluorescence microscopy. ...
Degradation of unwanted proteins is important in protein quality control cooperating with the dynein/dynactin-mediated trafficking along the acetylated microtubule (MT) network. Proteins associated directly/indirectly with tubulin/MTs play crucial roles in both physiological and pathological processes. Our studies focus on the interrelationship of the tubulin deacetylase HDAC6, the MT-associated TPPP/p25 with its deacetylase inhibitory potency and the hub dynein light chain DYNLL/LC8, constituent of dynein and numerous other protein complexes. In this paper, evidence is provided for the direct interaction of DYNLL/LC8 with TPPP/p25 and HDAC6 and their assembly into binary/ternary complexes with functional potency. The in vitro binding data was obtained with recombinant proteins and used for mathematical modelling. These data and visualization of their localizations by bimolecular fluorescence complementation technology and immunofluorescence microscopy in HeLa cells revealed the promoting effect of TPPP/p25 on the interaction of DYNLL/LC8 with both tubulin and HDAC6. Localization of the LC8-2-TPPP/p25 complex was observed on the MT network in contrast to the LC8-2-HDAC6 complex, which was partly translocated to the nucleus. LC8-2 did not influence directly the acetylation of the MT network. However, the binding of TPPP/p25 to a new binding site of DYNLL/LC8, outside the canonical binding groove, counteracted the TPPP/p25-derived hyperacetylation of the MT network. Our data suggest that multiple associations of the regulatory proteins of the MT network could ensure fine tuning in the regulation of the intracellular trafficking process either by the complexation of DYNLL/LC8 with new partners or indirectly by the modulation of the acetylation level of the MT network.
... Apart from the classical MAPs, there is also a unique family of highly conserved but not well-understood tubulin-binding proteins called the Tubulin Polymerization Promoting Proteins (TPPPs) that are implicated in the modulation and coordination of dynamics and stability of the MT network (Hlavanda et al., 2002;Tirián et al., 2003;Oláh et al., 2013) and display extensive MT bundling and polymerization abilities (Hlavanda et al., 2002;Lehotzky et al., 2010;Tokési et al., 2010;Zotter et al., 2011;Mino et al., 2016;Szabó et al., 2017). In addition to MT bundling activity, TPPPs have been implicated in regulating the levels of acetylation of MT network (Tokési et al., 2010;Szabó et al., 2017). ...
... Apart from the classical MAPs, there is also a unique family of highly conserved but not well-understood tubulin-binding proteins called the Tubulin Polymerization Promoting Proteins (TPPPs) that are implicated in the modulation and coordination of dynamics and stability of the MT network (Hlavanda et al., 2002;Tirián et al., 2003;Oláh et al., 2013) and display extensive MT bundling and polymerization abilities (Hlavanda et al., 2002;Lehotzky et al., 2010;Tokési et al., 2010;Zotter et al., 2011;Mino et al., 2016;Szabó et al., 2017). In addition to MT bundling activity, TPPPs have been implicated in regulating the levels of acetylation of MT network (Tokési et al., 2010;Szabó et al., 2017). Acetylation of MTs is evolutionarily conserved and represents one of the diverse post-translational modifications conferred to MTs. ...
... Having established Ringer localization, phenotypic and functional consequences of its loss from the presynaptic NMJ terminals, we next set out to investigate what other protein/s Ringer might be functioning with in regulating MT cytoskeleton and synaptic growth. Vertebrate TPPPs and MAP1B and their respective Drosophila homologs, Ringer and Futsch, display phenotypic and functional similarities in neurite outgrowth and axonal MT organization Tokési et al., 2010;Aoki et al., 2014;Villarroel-Campos and Gonzalez-Billault, 2014;Mino et al., 2016;Szabó et al., 2017;Tymanskyj et al., 2017). More importantly, Futsch was also reported to regulate synaptic MT organization and growth Roos et al., 2000;Ruiz-Canada et al., 2004). ...
Drosophila Ringmaker (Ringer) is homologous to the human Tubulin Polymerization Promoting Proteins (TPPPs) that are implicated in the stabilization and bundling of microtubules (MTs) that are particularly important for neurons and are also implicated in synaptic organization and plasticity. No in vivo functional data exist that have addressed the role of TPPP in synapse organization in any system. Here, we present the phenotypic and functional characterization of ringer mutants during Drosophila larval neuromuscular junction (NMJ) synaptic development. ringer mutants show reduced synaptic growth and transmission and display phenotypic similarities and genetic interactions with the Drosophila homolog of vertebrate Microtubule Associated Protein (MAP)1B, futsch. Immunohistochemical and biochemical analyses show that individual and combined loss of Ringer and Futsch cause a significant reduction in MT loops at the NMJs and reduced acetylated-tubulin levels. Presynaptic over-expression of Ringer and Futsch causes elevated levels of acetylated-tubulin and significant increase in NMJ MT loops. These results indicate that Ringer and Futsch regulate synaptic MT organization in addition to synaptic growth. Together our findings may inform studies on the close mammalian homolog, TPPP, and provide insights into the role of MTs and associated proteins in synapse growth and organization.
... A conjugation of a SirReal with a thalidomide moiety allowed the development of a proteolysis targeting chimera (PRO-TAC) dSIRT2 (22b) that chemically induced the proteasomal degradation of Sirt2 [96 ]. This tool enabled the discovery of the interplay between Sirt2 and TPPP/p25 that is dependent on the scaffolding functions of Sirt2, and not linked to its catalytic activity [97]. After the existence of the Sirt2 selectivity pocket was reported, it was shown that other substrates and ligands also gain their Sirt2 selectivity by targeting this pocket [98,99 ,100]. ...
Lysine acetylation has emerged as a key post-translational modification found at many sites throughout the cell. It plays an important role in epigenetic processes, and more generally in the regulation of protein stability and interactions. Acetyl groups are installed by lysine acetyltransferases and removed by lysine deacetylases. Acetylated lysine residues function as binding sites for bromodomains, which are epigenetic reader protein modules that mediate protein-protein interactions. Progress in the development of small molecules that interfere with lysine acetylation has stimulated intensive research activity in diverse therapeutic areas. Some of these compounds are already marketed as drugs or are undergoing clinical trials. Here we review recent progress in the development of small molecules that interfere with lysine acetylation state and acetyl-lysine reading by bromodomains. Address
Sirtuins are Class III protein deacetylases with seven conserved isoforms. In general, Sirtuins are highly activated under cellular stress conditions in which NAD⁺ levels are increased. Nevertheless, regulation of Sirtuins extends far beyond the influences of cellular NAD⁺/NADH ratio and a rapidly expanding body of evidence currently suggests that their expression and catalytic activity are highly kept under control at multiple levels by various factors and processes. Owing to their intrinsic ability to enzymatically target various intracellular proteins, Sirtuins are prominently involved in the regulation of fundamental biological processes including inflammation, metabolism, redox homeostasis, DNA repair and cell proliferation and senescence. In fact, Sirtuins are well established to regulate and reprogram different redox and metabolic pathways under both pathological and physiological conditions. Therefore, alterations in Sirtuin levels can be a pivotal intermediary step in the pathogenesis of several disorders. This review first highlights the mechanisms involved in the regulation of Sirtuins and further summarizes the current findings on the major functions of Sirtuins in cellular redox homeostasis and bioenergetics (glucose and lipid metabolism).
