Cargando…

Modulation Of Microtubule Acetylation By The Interplay Of TPPP/p25, SIRT2 And New Anticancer Agents With Anti-SIRT2 Potency

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Szabó, Adél, Oláh, Judit, Szunyogh, Sándor, Lehotzky, Attila, Szénási, Tibor, Csaplár, Marianna, Schiedel, Matthias, Lőw, Péter, Jung, Manfred, Ovádi, Judit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719079/
https://www.ncbi.nlm.nih.gov/pubmed/29213065
http://dx.doi.org/10.1038/s41598-017-17381-3
_version_ 1783284430231568384
author Szabó, Adél
Oláh, Judit
Szunyogh, Sándor
Lehotzky, Attila
Szénási, Tibor
Csaplár, Marianna
Schiedel, Matthias
Lőw, Péter
Jung, Manfred
Ovádi, Judit
author_facet Szabó, Adél
Oláh, Judit
Szunyogh, Sándor
Lehotzky, Attila
Szénási, Tibor
Csaplár, Marianna
Schiedel, Matthias
Lőw, Péter
Jung, Manfred
Ovádi, Judit
author_sort Szabó, Adél
collection PubMed
description 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 acting as dominant factors in the organization of myelin proteome. Herein, we show that SIRT2 impedes the TPPP/p25-promoted microtubule assembly independently of NAD(+); however, the TPPP/p25-assembled tubulin ultrastructures were resistant against SIRT2 activity. TPPP/p25 counteracts the SIRT2-derived tubulin deacetylation producing enhanced microtubule acetylation. The inhibition of the SIRT2 deacetylase activity by TPPP/p25 is evolved by the assembly of these tubulin binding proteins into a ternary complex, the concentration-dependent formation of which was quantified by experimental-based mathematical modelling. Co-localization of the SIRT2-TPPP/p25 complex on the microtubule network was visualized in HeLa cells by immunofluorescence microscopy using Bimolecular Fluorescence Complementation. We also revealed that a new potent SIRT2 inhibitor (MZ242) and its proteolysis targeting chimera (SH1) acting together with TPPP/p25 provoke microtubule hyperacetylation, which is coupled with process elongation only in the case of the degrader SH1. Both the structural and the functional effects manifesting themselves by this deacetylase proteome could lead to the fine-tuning of the regulation of microtubule dynamics and stability.
format Online
Article
Text
id pubmed-5719079
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-57190792017-12-08 Modulation Of Microtubule Acetylation By The Interplay Of TPPP/p25, SIRT2 And New Anticancer Agents With Anti-SIRT2 Potency Szabó, Adél Oláh, Judit Szunyogh, Sándor Lehotzky, Attila Szénási, Tibor Csaplár, Marianna Schiedel, Matthias Lőw, Péter Jung, Manfred Ovádi, Judit Sci Rep Article 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 acting as dominant factors in the organization of myelin proteome. Herein, we show that SIRT2 impedes the TPPP/p25-promoted microtubule assembly independently of NAD(+); however, the TPPP/p25-assembled tubulin ultrastructures were resistant against SIRT2 activity. TPPP/p25 counteracts the SIRT2-derived tubulin deacetylation producing enhanced microtubule acetylation. The inhibition of the SIRT2 deacetylase activity by TPPP/p25 is evolved by the assembly of these tubulin binding proteins into a ternary complex, the concentration-dependent formation of which was quantified by experimental-based mathematical modelling. Co-localization of the SIRT2-TPPP/p25 complex on the microtubule network was visualized in HeLa cells by immunofluorescence microscopy using Bimolecular Fluorescence Complementation. We also revealed that a new potent SIRT2 inhibitor (MZ242) and its proteolysis targeting chimera (SH1) acting together with TPPP/p25 provoke microtubule hyperacetylation, which is coupled with process elongation only in the case of the degrader SH1. Both the structural and the functional effects manifesting themselves by this deacetylase proteome could lead to the fine-tuning of the regulation of microtubule dynamics and stability. Nature Publishing Group UK 2017-12-06 /pmc/articles/PMC5719079/ /pubmed/29213065 http://dx.doi.org/10.1038/s41598-017-17381-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Szabó, Adél
Oláh, Judit
Szunyogh, Sándor
Lehotzky, Attila
Szénási, Tibor
Csaplár, Marianna
Schiedel, Matthias
Lőw, Péter
Jung, Manfred
Ovádi, Judit
Modulation Of Microtubule Acetylation By The Interplay Of TPPP/p25, SIRT2 And New Anticancer Agents With Anti-SIRT2 Potency
title Modulation Of Microtubule Acetylation By The Interplay Of TPPP/p25, SIRT2 And New Anticancer Agents With Anti-SIRT2 Potency
title_full Modulation Of Microtubule Acetylation By The Interplay Of TPPP/p25, SIRT2 And New Anticancer Agents With Anti-SIRT2 Potency
title_fullStr Modulation Of Microtubule Acetylation By The Interplay Of TPPP/p25, SIRT2 And New Anticancer Agents With Anti-SIRT2 Potency
title_full_unstemmed Modulation Of Microtubule Acetylation By The Interplay Of TPPP/p25, SIRT2 And New Anticancer Agents With Anti-SIRT2 Potency
title_short Modulation Of Microtubule Acetylation By The Interplay Of TPPP/p25, SIRT2 And New Anticancer Agents With Anti-SIRT2 Potency
title_sort modulation of microtubule acetylation by the interplay of tppp/p25, sirt2 and new anticancer agents with anti-sirt2 potency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719079/
https://www.ncbi.nlm.nih.gov/pubmed/29213065
http://dx.doi.org/10.1038/s41598-017-17381-3
work_keys_str_mv AT szaboadel modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency
AT olahjudit modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency
AT szunyoghsandor modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency
AT lehotzkyattila modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency
AT szenasitibor modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency
AT csaplarmarianna modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency
AT schiedelmatthias modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency
AT lowpeter modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency
AT jungmanfred modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency
AT ovadijudit modulationofmicrotubuleacetylationbytheinterplayoftpppp25sirt2andnewanticanceragentswithantisirt2potency