title: Accumulation of the PX domain mutant Frank-ter Haar syndrome protein Tks4 in aggresomes.
abstract: BACKGROUND
  Cells 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.
  
  
  RESULTS
  Here we demonstrate that the accumulation of Tks4(R43W) 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 Tks4(R43W). Finally, pretreatment of cells with the proteasome inhibitor MG132 markedly increases the level of aggresomes formed by Tks4(R43W). Furthermore, two additional mutant Tks4 proteins (Tks4(1-48) or Tks4(1-341)) have been investigated. Whereas the shorter Tks4 mutant, Tks4(1-48), shows no expression at all, the longer Tks4 truncation mutant accumulates in the nuclei of the cells.
  
  
  CONCLUSIONS
  Our results suggest that misfolded Frank-ter Haar syndrome protein Tks4(R43W) is transported via the microtubule system to the aggresomes. Lack of expression of Tks4(1-48) or aberrant intracellular expressions of Tks4(R43W) and Tks4(1-341) strongly suggest that these mutations result in dysfunctional proteins which are not capable of operating properly, leading to the development of FTHS.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: Csaba
authors.initials: C
authors.lastname: Ádám
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: Anna
authors.initials: A
authors.lastname: Fekete
authors.affiliation: Department of Medical Chemistry, Semmelweis University Medical School, Budapest, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Bőgel
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Németh
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: Natália
authors.initials: N
authors.lastname: Tőkési
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: Judit
authors.initials: J
authors.lastname: Ovádi
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: Károly
authors.initials: K
authors.lastname: Liliom
authors.affiliation: Department of Medical Chemistry, Semmelweis University Medical School, Budapest, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Pesti
authors.affiliation: Department of Physiology, Semmelweis University Medical School, Budapest, Hungary. buday.laszlo@ttk.mta.hu.|"Lendület" Peroxidase Enzyme Research Group of the Semmelweis University and the Hungarian Academy of Sciences, Budapest, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: Miklós
authors.initials: M
authors.lastname: Geiszt
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary. buday.laszlo@ttk.mta.hu.|Department of Medical Chemistry, Semmelweis University Medical School, Budapest, Hungary. buday.laszlo@ttk.mta.hu.
authors.forename: László
authors.initials: L
authors.lastname: Buday
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002658:Developmental Disabilities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008870:Microtubules / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010009:Osteochondrodysplasias / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C547814:SH3PXD2B protein, human