Regulation of Intracellular Trafficking of Huntingtin-Associated Protein-1 Is Critical for TrkA Protein Levels and Neurite Outgrowth

Abstract

Mutant huntingtin can affect vesicular and receptor trafficking via its abnormal protein interactions, suggesting that impairment of intracellular trafficking may contribute to Huntington's disease. There is growing evidence that huntingtin-associated protein-1 (HAP1) also interacts with microtubule-dependent transporters and is involved in intracellular trafficking. However, it remains unclear how the trafficking of HAP1 is regulated and contributes to neuronal function. Here we report that phosphorylation of HAP1 decreases its association with microtubule-dependent transport proteins dynactin p150 and kinesin light chain and reduces its localization in neurite tips. Suppressing HAP1 expression by RNA interference reduces neurite outgrowth and the level of tropomyosin-related kinase A receptor tyrosine kinase (TrkA), a nerve growth factor receptor whose internalization and trafficking are required for neurite outgrowth. HAP1 maintains the normal level of membrane TrkA by preventing the degradation of internalized TrkA. Mutant huntingtin also reduces the association of HAP1 with dynactin p150 and kinesin light chain and thereby decreases the intracellular level of TrkA. These findings suggest that HAP1 trafficking is critical for the stability of TrkA and neurite function, both of which can be attenuated by mutant huntingtin.

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

“…Thus, we concluded that Hap1 not only sequesters but also stabilizes Dcaf7 in the cytoplasm by inhibiting its degradation by the UPS. Because Hap1 can protect internalized receptors from lysosomal degradation (11,(29)(30)(31), Hap1 may stabilize its binding partners from subsequent degradation through either the lysosome or UPS.…”

Troyer Syndrome Protein Spartin Is Mono-Ubiquitinated and Functions in EGF Receptor Trafficking

“…Another possible role for spartin in neurons may be in the internalization, sorting, and/or degradation of specific receptors for neurotrophic factors such as BDNF or NGF, which are important for cell survival and neurite outgrowth. Interestingly, a number of proteins mutated in neurological disorders, including alsin, huntingtin, and parkin, have roles in endocytosis (Devon et al, 2006;Fallon et al, 2006;Rong et al, 2006). It remains to be determined whether lack of spartin affects endocytosis of growth factor receptors, which might lead to deficiency in survival signals and impaired neurite outgrowth.…”

SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease

“…HTT protein is a scaffolding protein that regulates multiple aspects of trafficking of transmembrane receptors, including endocytosis (82), endosomal sorting (83), anterograde transport (71,84), degradation (71,83,84), and recycling (85,86). It has been shown that mtHTT can inhibit the surface expression of receptors via its interactions with trafficking proteins such as Rab11 (87) and HAP1 (71,83,84), proteins that prevent lysosomal degradation and promote recycling of their cargo receptors back to the cell surface (88). For example, mtHTT can bind to and interfere with the nucleotide exchange activity of Rab11, a small GTPase that functions at recycling endosomes, and impede the membrane recycling of its cargo such as transferrin receptor (89), solute carrier EAAC1 (87), and glucose transporter 3 (90).…”

“…For example, mtHTT can bind to and interfere with the nucleotide exchange activity of Rab11, a small GTPase that functions at recycling endosomes, and impede the membrane recycling of its cargo such as transferrin receptor (89), solute carrier EAAC1 (87), and glucose transporter 3 (90). mtHTT also binds more tightly to HAP1 compared with wtHTT, thereby disrupting the synaptic targeting of GABA A receptor (83) and the anterograde trafficking of TrkA receptor (84).…”