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

Szabolcs Pesti,Natália Tőkési,Judit Ovádi,Anna Fekete,Károly Liliom,Zsuzsanna Németh,László Buday,Csaba Ádám,Miklós Geiszt,Gábor Bőgel

doi:10.1186/s12964-015-0108-8

Abstract

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.

Highlights

Cells deploy quality control mechanisms to remove damaged or misfolded proteins
The misfolded Tyrosine kinase substrate with four SH3 domains (Tks4) mutant colocalizes with the microtubule-organizing center (MTOC) and its aggregate is encaged by the intermediate filament protein vimentin
Tks4R43W displays characteristics of misfolding In 2010, Iqbal and colleagues have identified a patient with Frank-ter Haar syndrome (FTHS) whose SH3PXD2B gene contains a substitution mutation which results in the change of the conserved arginine 43 to tryptophan in the PX domain

Summary

Introduction

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 Tks resulted in aberrant intracellular localization. Cells deploy quality control mechanisms to remove damaged or misfolded proteins These mechanisms include up-regulated chaperones to facilitate protein refolding, ubiquitin-dependent degradation of misfolded/damaged proteins, and formation of detergent insoluble aggresomes at the juxtanuclear region [1,2,3,4]. Aggresome formation is a vital mechanism to eliminate misfolded proteins, it is not clear if it is an independent process or it is activated only when the degradative capacity of the ubiquitin-proteasome system is overwhelmed [5]. In this system, misfolded and aggregated proteins are selectively recognized, ubiquitinated, and delivered via HDAC6. The accumulation of protein aggregates is commonly linked with various human diseases referred to as protein conformation disorders [7]

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