Mutant huntingtin impairs post-golgi trafficking to lysosomes by delocalizing optineurin/rab8 complex from the golgi apparatus

Daniel Del Toro, Jordi Alberch, Francisco Lazaro-Dieguez, Raquel Martin-Ibaflez, Xavier Xifro, Gustavo Egea, Josep M. Canals

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1478-1492
Number of pages15
JournalMolecular biology of the cell
Volume20
Issue number5
DOIs
StatePublished - Mar 1 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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