Hook2 contributes to aggresome formation

Györgyi Szebenyi,Helmut Krämer,W Christian Wigley,Michelle Yu,Aaron Didier,Branden Hall,Philip Thomas

doi:10.1186/1471-2121-8-19

Abstract

BackgroundAggresomes are pericentrosomal accumulations of misfolded proteins, chaperones and proteasomes. Their positioning near the centrosome, like that of other organelles, requires active, microtubule-dependent transport. Linker proteins that can associate with the motor protein dynein, organelles, and microtubules are thought to contribute to the active maintenance of the juxtanuclear localization of many membrane bound organelles and aggresomes. Hook proteins have been proposed to serve as adaptors for the association of cargos with dynein for transport on microtubules. Hook2 was shown to localize to the centrosome, bind centriolin, and contribute to centrosomal function.ResultsHere we show that overexpression of hook2 promotes the accumulation of the cystic fibrosis transmembrane regulator in aggresomes without altering its biochemical properties or its steady state level. A dominant negatively acting form of hook2 that lacks the centriolin binding C-terminal inhibits aggresome formation.ConclusionWe propose that hook2 contributes to the establishment and maintenance of the pericentrosomal localization of aggresomes by promoting the microtubule-based delivery of protein aggregates to pericentriolar aggresomes.

Highlights

Aggresomes are pericentrosomal accumulations of misfolded proteins, chaperones and proteasomes
The juxtanuclear localization of over-expressed hook2-constructs resembled the centrosomal distribution of endogenous hook2 in an accentuated form [Fig. 1A and ref. [21]]
We have previously shown that centrosomal accumulation of hook2 did not disrupt the microtubule network or the Golgi complex [21], indicating that hook2 overexpression did not disrupt the structural integrity of cells

Summary

Introduction

Aggresomes are pericentrosomal accumulations of misfolded proteins, chaperones and proteasomes Their positioning near the centrosome, like that of other organelles, requires active, microtubule-dependent transport. Similar to some other integral membrane proteins that have large hydrophobic regions [12], over-expressed CFTR is inefficiently processed [13] This is even more pronounced for a prevalent mutation in cystic fibrosis patients, the ∆F508-CFTR deletion mutant, which is degraded by the proteasome [14,15]. The retrograde transport of CFTR and other misfolded proteins depends on the integrity of the microtubule cytoskeleton and the association of dynein with the cargo-binding dynactin complex [4,16,17]

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Results

Conclusion