605, Pal et al. report that Huntingtin (Htt) and its associated protein HAP40 are part of the machinery used by Rab5 to control switching between microtubules and actin filaments. The data may explain why vesicle motility is disrupted in Htt mutant cells.
When Pal et al. went looking for Rab5 effector proteins by affinity chromatography, they isolated HAP40 and Htt. Biochemical analysis showed that HAP40 acts as a bridge between Rab5 and Htt in a GTP-dependent manner. Excess HAP40 drives the vesicles off microtubules and onto actin filaments, reducing the vesicles' motility. Addition of an antibody against Htt relieved the transport restriction, suggesting that Htt negatively regulates the link between endosome and microtubules.
Surprisingly, HAP40 expression was tenfold higher in cells isolated from Huntington patients as compared with cells from healthy volunteers. Such Htt mutant cells had reduced endocytosis and endosome motility.
In wild-type cells, a small amount of Htt protein on endosomes works with HAP40 and Rab5 to regulate motility; however, the up-regulation of HAP40 in Huntington disease cells is necessary and sufficient to arrest endosome motility. The team now wants to know just how restricted endosome motility might impact Huntington disease pathology and why HAP40 is overexpressed in Htt mutant cells.