Accumulation of the PX domain mutant Frank-ter Haar syndrome protein Tks4 in aggresomes

Cell Communication and Signaling

Research Article

Szabolcs Pesti¹  Gábor Bőgel¹  Miklós Geiszt²  Zsuzsanna Németh³  Judit Ovádi³  Csaba Ádám³  Anna Fekete³  Károly Liliom³  Natália Tőkési³  László Buday⁴ 

[1] Department of Medical Chemistry, Semmelweis University Medical School, Budapest, Hungary;Department of Physiology, Semmelweis University Medical School, Budapest, Hungary;“Lendület” Peroxidase Enzyme Research Group of the Semmelweis University and the Hungarian Academy of Sciences, Budapest, Hungary;Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117, Budapest, Hungary;Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117, Budapest, Hungary;Department of Medical Chemistry, Semmelweis University Medical School, Budapest, Hungary;

关键词: Tks4;    Aggresome;    Frank-ter Haar Syndrome;    Microtubules;    Misfolded protein;   

DOI  :  10.1186/s12964-015-0108-8

 received in 2015-04-01, accepted in 2015-06-22,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundCells deploy quality control mechanisms to remove damaged or misfolded proteins. Recently, we have reported that a mutation (R43W) in the Frank-ter Haar syndrome protein Tks4 resulted in aberrant intracellular localization.ResultsHere we demonstrate that the accumulation of Tks4R43W depends on the intact microtubule network. Detergent-insoluble Tks4 mutant colocalizes with the centrosome and its aggregate is encaged by the intermediate filament protein vimentin. Both the microtubule inhibitor nocodazole and the histone deacetylase inhibitor Trichostatin A inhibit markedly the aggresome formation in cells expressing Tks4R43W. Finally, pretreatment of cells with the proteasome inhibitor MG132 markedly increases the level of aggresomes formed by Tks4R43W. Furthermore, two additional mutant Tks4 proteins (Tks41–48 or Tks41–341) have been investigated. Whereas the shorter Tks4 mutant, Tks41–48, shows no expression at all, the longer Tks4 truncation mutant accumulates in the nuclei of the cells.ConclusionsOur results suggest that misfolded Frank-ter Haar syndrome protein Tks4R43W is transported via the microtubule system to the aggresomes. Lack of expression of Tks41–48 or aberrant intracellular expressions of Tks4R43W and Tks41–341 strongly suggest that these mutations result in dysfunctional proteins which are not capable of operating properly, leading to the development of FTHS.

【 授权许可】

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© Ádám et al. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.