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Review
. 2009 Apr;19(4):147-55.
doi: 10.1016/j.tcb.2009.01.005. Epub 2009 Mar 5.

Huntingtin as an essential integrator of intracellular vesicular trafficking

Juliane P Caviston  1 , Erika L F Holzbaur
Affiliations
Review

Huntingtin as an essential integrator of intracellular vesicular trafficking

Juliane P Caviston et al. Trends Cell Biol. 2009 Apr.

Abstract

The neurodegenerative disorder Huntington's disease is caused by an expansion in the polyglutamine repeat region of the protein huntingtin. Multiple studies in cellular and animal model systems indicate that this mutation imparts a novel toxic function required for disease pathogenesis. However, the normal function of huntingtin, an essential cellular protein in higher vertebrates, is not yet well understood. Emerging data indicate an important role for wild-type huntingtin in the intracellular transport of vesicles and organelles. Here, we discuss current progress on the role of huntingtin in vesicular trafficking, focusing on the proposal that huntingtin might be a crucial regulator of organelle transport along the cellular cytoskeleton.

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Figures

Figure 1
Figure 1
Schematic of huntingtin with binding sites for molecular motor and motor-associated proteins denoted. The N-terminal ER localization signal (aa1–18){Atwal 2007} is shown in green and the polyglutamine repeat region is shown in red. Normal huntingtin contains 35 or fewer polyglutamines and 36 or more has been associated with HD{Imarisio 2008}. The myosin VI linker protein optineurin is known to associate with the N-terminal region of huntingtin. HAP1 also interacts with the N-terminal region of huntingtin and directly interacts with the plus-end-directed microtubule motor kinesin as well as dynactin. The minus-end-directed microtubule motor dynein interacts with huntingtin (aa600–698) and with the dynein activator dynactin. Huntingtin is phosphorylated on serine 421 (yellow circle). HAP40, an effector of the small GTPase Rab5, binds to the C-terminal region of huntingtin.
Figure 2
Figure 2
Three models for how huntingtin, by acting as a scaffold to coordinate the interplay of various molecular motor and motor-associated proteins, facilitates vesicular transport along the cytoskeleton. (a) Model 1: Huntingtin phosphorylation is a molecular switch. When huntingtin is phosphorylated at serine 421, kinesin is recruited to vesicles, and anterograde vesicle motility along the microtubule towards the plus-end predominates. In the unphosphorylated state, kinesin recruitment to the vesicle is no longer stabilized, and dynein dynactin-mediated retrograde motility towards the minus-end predominates. (b) Model 2: The huntingtin HAP40 complex on Rab5-associated endosomes is a switch for cytoskeletal affinity between actin and microtubules. When there is an increase in cytoplasmic levels of HAP40, the early endosome positive for Rab5 is able to associate with actin, possibly through a linker, such as optineurin, that binds to myosin VI. When HAP40 levels are decreased, Rab5-positive early endosomes bind to the microtubule. (c) Model 3: Huntingtin coordinates cytoskeletal vesicle transport. When endocytic cargo traverses the actin cytoskeleton, huntingtin may mediate vesicle attachment to actin via a myosin adaptor protein as in (b). Upon loss of HAP40, and perhaps binding of HAP1, microtubule affinity is enhanced; additional regulatory events, such as phosphorylation of huntingtin as in (a), influence what microtubule motor will predominate, and contribute to the directionality of transport,.
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