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Article

Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein

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Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Molecular Proteomics Laboratory, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Department of Otolaryngology and Head/Neck Surgery, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Institute for Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Department of Pediatrics III, University Hospital Essen, University Duisburg-Essen, 45112 Essen, Germany
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Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
*
Author to whom correspondence should be addressed.
Current address: Department of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
Cells 2020, 9(9), 1950; https://doi.org/10.3390/cells9091950
Received: 25 May 2020 / Revised: 14 August 2020 / Accepted: 21 August 2020 / Published: 24 August 2020
(This article belongs to the Special Issue Centrosome)
The stress-inducible and senescence-associated tumor suppressor SIRT4, a member of the family of mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5), regulates bioenergetics and metabolism via NAD+-dependent enzymatic activities. Next to the known mitochondrial location, we found that a fraction of endogenous or ectopically expressed SIRT4, but not SIRT3, is present in the cytosol and predominantly localizes to centrosomes. Confocal spinning disk microscopy revealed that SIRT4 is found during the cell cycle dynamically at centrosomes with an intensity peak in G2 and early mitosis. Moreover, SIRT4 precipitates with microtubules and interacts with structural (α,β-tubulin, γ-tubulin, TUBGCP2, TUBGCP3) and regulatory (HDAC6) microtubule components as detected by co-immunoprecipitation and mass spectrometric analyses of the mitotic SIRT4 interactome. Overexpression of SIRT4 resulted in a pronounced decrease of acetylated α-tubulin (K40) associated with altered microtubule dynamics in mitotic cells. SIRT4 or the N-terminally truncated variant SIRT4(ΔN28), which is unable to translocate into mitochondria, delayed mitotic progression and reduced cell proliferation. This study extends the functional roles of SIRT4 beyond mitochondrial metabolism and provides the first evidence that SIRT4 acts as a novel centrosomal/microtubule-associated protein in the regulation of cell cycle progression. Thus, stress-induced SIRT4 may exert its role as tumor suppressor through mitochondrial as well as extramitochondrial functions, the latter associated with its localization at the mitotic spindle apparatus. View Full-Text
Keywords: sirtuin; SIRT4; interactome; centrosome; mitosis; HDAC6 sirtuin; SIRT4; interactome; centrosome; mitosis; HDAC6
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MDPI and ACS Style

Bergmann, L.; Lang, A.; Bross, C.; Altinoluk-Hambüchen, S.; Fey, I.; Overbeck, N.; Stefanski, A.; Wiek, C.; Kefalas, A.; Verhülsdonk, P.; Mielke, C.; Sohn, D.; Stühler, K.; Hanenberg, H.; Jänicke, R.U.; Scheller, J.; Reichert, A.S.; Ahmadian, M.R.; Piekorz, R.P. Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein. Cells 2020, 9, 1950. https://doi.org/10.3390/cells9091950

AMA Style

Bergmann L, Lang A, Bross C, Altinoluk-Hambüchen S, Fey I, Overbeck N, Stefanski A, Wiek C, Kefalas A, Verhülsdonk P, Mielke C, Sohn D, Stühler K, Hanenberg H, Jänicke RU, Scheller J, Reichert AS, Ahmadian MR, Piekorz RP. Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein. Cells. 2020; 9(9):1950. https://doi.org/10.3390/cells9091950

Chicago/Turabian Style

Bergmann, Laura, Alexander Lang, Christoph Bross, Simone Altinoluk-Hambüchen, Iris Fey, Nina Overbeck, Anja Stefanski, Constanze Wiek, Andreas Kefalas, Patrick Verhülsdonk, Christian Mielke, Dennis Sohn, Kai Stühler, Helmut Hanenberg, Reiner U. Jänicke, Jürgen Scheller, Andreas S. Reichert, Mohammad R. Ahmadian, and Roland P. Piekorz. 2020. "Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein" Cells 9, no. 9: 1950. https://doi.org/10.3390/cells9091950

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