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

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

Authors :
Mohammad Reza Ahmadian
Helmut Hanenberg
Nina Overbeck
Andreas Kefalas
Alexander Lang
Patrick Verhülsdonk
Anja Stefanski
Jürgen Scheller
Kai Stühler
Andreas S. Reichert
Constanze Wiek
Simone Altinoluk-Hambüchen
Christoph Bross
Christian Mielke
Laura Bergmann
Iris Fey
Reiner U. Jänicke
Dennis Sohn
Roland P. Piekorz
Source :
Cells, Vol 9, Iss 1950, p 1950 (2020), Cells, Volume 9, Issue 9
Publication Year :
2020

Abstract

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 (&alpha<br />&beta<br />tubulin, &gamma<br />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 &alpha<br />tubulin (K40) associated with altered microtubule dynamics in mitotic cells. SIRT4 or the N-terminally truncated variant SIRT4(&Delta<br />N28), 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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Cells, Vol 9, Iss 1950, p 1950 (2020), Cells, Volume 9, Issue 9
Accession number :
edsair.doi.dedup.....2a7918a082681010a9257a4e45e90c12