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Published 13 February 2006. doi:10.1083/jcb.200509091
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 4, 605-618
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Article

Huntingtin–HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington's disease



Arun Pal, Fedor Severin, Barbara Lommer, Anna Shevchenko, and Marino Zerial

Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany

Correspondence to Marino Zerial: zerial{at}mpi-cbg.de

The molecular mechanisms underlying the targeting of Huntingtin (Htt) to endosomes and its multifaceted role in endocytosis are poorly understood. In this study, we have identified Htt-associated protein 40 (HAP40) as a novel effector of the small guanosine triphosphatase Rab5, a key regulator of endocytosis. HAP40 mediates the recruitment of Htt by Rab5 onto early endosomes. HAP40 overexpression caused a drastic reduction of early endosomal motility through their displacement from microtubules and preferential association with actin filaments. Remarkably, endogenous HAP40 was up-regulated in fibroblasts and brain tissue from human patients affected by Huntington's disease (HD) as well as in STHdhQ111 striatal cells established from a HD mouse model. These cells consistently displayed altered endosome motility and endocytic activity, which was restored by the ablation of HAP40. In revealing an unexpected link between Rab5, HAP40, and Htt, we uncovered a new mechanism regulating cytoskeleton-dependent endosome dynamics and its dysfunction under pathological conditions.

F. Severin's present address is Biotechnology Centre, University of Technology Dresden, Cellular Machines, 01307 Dresden, Germany.

Abbreviations used in this paper: EEA1, early endosome antigen 1; F-actin, filamentous actin; GDI, GDP dissociation inhibitor; GDP, guanosine diphosphate; HAP, Htt-associated protein; HD, Huntington's disease; HIP; Htt-interacting protein; Htt, Huntingtin; LAMP, lysosome-associated membrane protein; polyQ, polyglutamine; RNAi, RNA interference; siRNA, short interfering RNA; Tfr, transferrin receptor.


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