Huntingtin facilitates dynein/dynactin-mediated vesicle transport

Caviston, Juliane P.; Ross, Jennifer L.; Antony, Sheila Maria da Rocha; Tokito, Mariko; Holzbaur, Erika L.F.

doi:10.1073/pnas.0610628104

Cited by 260 publications

(223 citation statements)

References 31 publications

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“…To further corroborate this hypothesis, we next investigated the effects of depleting htt by siRNA. Consistent with previous studies (Caviston et al, 2007), we observed that wt cells transfected with htt siRNA showed partial Golgi disruption. Interestingly, the colocalization between optineurin and GT-YFP was lower in wt cells with reduced expression of htt with respect to those transfected with control siRNA (Figure 4C), indicating that htt is implicated in the localization of optineurin at the Golgi apparatus.…”

Section: Mhtt Reduces the Presence Of Optineurin And Rab8 In The Golgsupporting

confidence: 82%

“…Electron microscopy images showed partial disruption of the Golgi apparatus that could be related to the reduction of optineurin and htt in this apparatus. In fact, depletion of optineurin or htt results in Golgi disorganization (Sahlender et al, 2005;Caviston et al, 2007). Interestingly, there is an abnormal increase in CCVs in the proximity of the TGN in mhtt cells.…”

Section: Discussionmentioning

confidence: 99%

“…Htt is a cytosolic protein that has been associated not only with the Golgi apparatus (Difiglia et al, 1995;Caviston et al, 2007) but also with exocytic vesicles (Gauthier et al, 2004). To study the mechanism by which mhtt impairs post-Golgi trafficking, we first performed colocalization studies between htt and GT-YFP, which specifically labels the Golgi apparatus, in knockin wt and mhtt cells.…”

Section: Mhtt Is Delocalized From the Golgi Apparatusmentioning

confidence: 99%

“…NM_010414): 5Ј-agagcuaggcacacugcucat-3Ј, 5Ј-aaaacuacccucuggaugugg-3Ј, 5Ј-uuaacaaggcuugucccaaag-3Ј, 5Ј-acaacatctgtacaattgcag-3Ј as described previously (Caviston et al, 2007). Control cells were transfected with nontargeting RNA duplex oligonucleotides.…”

Section: Small Interfering Rna (Sirna) Transfectionmentioning

confidence: 99%

“…However, the molecular mechanism by which htt participates in post-Golgi trafficking remains unclear. Htt colocalizes with the Golgi apparatus and with exocytic vesicles (Difiglia et al, 1995) and reduced expression of htt by RNA interference (RNAi) disrupts the Golgi apparatus (Caviston et al, 2007). Moreover, several htt-interacting proteins, such as HIP14 (Singaraja et al, 2002) and optineurin (Hattula and Peranen, 2000), contribute to the function of the Golgi apparatus and exocytosis.…”

Section: Introductionmentioning

confidence: 99%

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Mutant Huntingtin Impairs Post-Golgi Trafficking to Lysosomes by Delocalizing Optineurin/Rab8 Complex from the Golgi Apparatus

Toro

Alberch

Lázaro‐Diéguez

et al. 2009

MBoC

148

115

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Huntingtin regulates post-Golgi trafficking of secreted proteins. Here, we studied the mechanism by which mutant huntingtin impairs this process. Colocalization studies and Western blot analysis of isolated Golgi membranes showed a reduction of huntingtin in the Golgi apparatus of cells expressing mutant huntingtin. These findings correlated with a decrease in the levels of optineurin and Rab8 in the Golgi apparatus that can be reverted by overexpression of full-length wild-type huntingtin. In addition, immunoprecipitation studies showed reduced interaction between mutant huntingtin and optineurin/Rab8. Cells expressing mutant huntingtin produced both an accumulation of clathrin adaptor complex 1 at the Golgi and an increase of clathrin-coated vesicles in the vicinity of Golgi cisternae as revealed by electron microscopy. Furthermore, inverse fluorescence recovery after photobleaching analysis for lysosomal-associated membrane protein-1 and mannose-6-phosphate receptor showed that the optineurin/Rab8-dependent post-Golgi trafficking to lysosomes was impaired in cells expressing mutant huntingtin or reducing huntingtin levels by small interfering RNA. Accordingly, these cells showed a lower content of cathepsin D in lysosomes, which led to an overall reduction of lysosomal activity. Together, our results indicate that mutant huntingtin perturbs post-Golgi trafficking to lysosomal compartments by delocalizing the optineurin/Rab8 complex, which, in turn, affects the lysosomal function.

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Section: Mhtt Reduces the Presence Of Optineurin And Rab8 In The Golgsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Mhtt Is Delocalized From the Golgi Apparatusmentioning

confidence: 99%

Section: Small Interfering Rna (Sirna) Transfectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mutant Huntingtin Impairs Post-Golgi Trafficking to Lysosomes by Delocalizing Optineurin/Rab8 Complex from the Golgi Apparatus

Toro

Alberch

Lázaro‐Diéguez

et al. 2009

MBoC

148

115

View full text Add to dashboard Cite

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Huntingtin gene CAG repeat size affects autism risk: Family‐based and case–control association study

Piras

Picinelli²,

Iennaco

et al. 2020

American J of Med Genetics Pt B

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The Huntingtin (HTT) gene contains a CAG repeat in exon 1, whose expansion beyond 39 repeats consistently leads to Huntington's disease (HD), whereas normal‐to‐intermediate alleles seemingly modulate brain structure, function and behavior. The role of the CAG repeat in Autism Spectrum Disorder (ASD) was investigated applying both family‐based and case–control association designs, with the SCA3 repeat as a negative control. Significant overtransmission of “long” CAG alleles (≥17 repeats) to autistic children and of “short” alleles (≤16 repeats) to their unaffected siblings (all p < 10−5) was observed in 612 ASD families (548 simplex and 64 multiplex). Surprisingly, both 193 population controls and 1,188 neurological non‐HD controls have significantly lower frequencies of “short” CAG alleles compared to 185 unaffected siblings and higher rates of “long” alleles compared to 548 ASD patients from the same families (p < .05–.001). The SCA3 CAG repeat displays no association. “Short” HTT alleles seemingly exert a protective effect from clinically overt autism in families carrying a genetic predisposition for ASD, while “long” alleles may enhance autism risk. Differential penetrance of autism‐inducing genetic/epigenetic variants may imply atypical developmental trajectories linked to HTT functions, including excitation/inhibition imbalance, cortical neurogenesis and apoptosis, neuronal migration, synapse formation, connectivity and homeostasis.

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The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling

et al. 2013

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In Huntington disease (HD), polyglutamine expansion in the huntingtin protein causes specific neuronal death. The consequences of the presence of mutant huntingtin in other tissues are less well understood. Here we propose that mutant huntingtin influences breast cancer progression. Indeed, we show that mammary tumours appear earlier in mouse breast cancer models expressing mutant huntingtin as compared to control mice expressing wild-type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern that reflects enhanced aggressiveness with the overexpression of genes favouring invasion and metastasis. In agreement, mutant huntingtin accelerates epithelial to mesenchymal transition and enhances cell motility and invasion. Also, lung metastasis is higher in HD conditions than in control mice. Finally, we report that in HD, the dynamin dependent endocytosis of the ErbB2/HER2 receptor tyrosine kinase is reduced. This leads to its accumulation and to subsequent increases in cell motility and proliferation. Our study may thus have important implications for both cancer and HD.

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Huntingtin facilitates dynein/dynactin-mediated vesicle transport

Abstract: microtubule motility ͉ membrane trafficking ͉ molecular motors ͉ bidirectional motility ͉ Huntington's disease

Cited by 260 publications

References 31 publications

Mutant Huntingtin Impairs Post-Golgi Trafficking to Lysosomes by Delocalizing Optineurin/Rab8 Complex from the Golgi Apparatus

Mutant Huntingtin Impairs Post-Golgi Trafficking to Lysosomes by Delocalizing Optineurin/Rab8 Complex from the Golgi Apparatus

Huntingtin gene CAG repeat size affects autism risk: Family‐based and case–control association study

The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling

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