Hsc70 is required for endocytosis and clathrin function in <i>Drosophila </i>

Chang, Henry; Newmyer, Sherri L.; Hull, Michael; Ebersold, Melanie; Schmid, Sandra L.; Mellman, Ira

doi:10.1083/jcb.200205086

Cited by 121 publications

(134 citation statements)

References 56 publications

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“…In addition, some chaperones are known to be involved in essential cellular processes. For example, hsc70-4 in Drosophila is critical for clathrin-dependent endocytosis (Chang et al 2002(Chang et al , 2004. Thus, modulating the activities of these chaperones might indirectly affect the aggregates formation, and their observed differential effect on aggregation could be due to their distinctive cellular functions and substrate specificity.…”

Section: Resultsmentioning

confidence: 99%

A Genomewide RNA Interference Screen for Modifiers of Aggregates Formation by Mutant Huntingtin in Drosophila

Zhang¹,

Binari

Zhou³

et al. 2010

Genetics

146

176

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Protein aggregates are a common pathological feature of most neurodegenerative diseases (NDs). Understanding their formation and regulation will help clarify their controversial roles in disease pathogenesis. To date, there have been few systematic studies of aggregates formation in Drosophila, a model organism that has been applied extensively in modeling NDs and screening for toxicity modifiers. We generated transgenic fly lines that express enhanced-GFP-tagged mutant Huntingtin (Htt) fragments with different lengths of polyglutamine (polyQ) tract and showed that these Htt mutants develop protein aggregates in a polyQ-length-and age-dependent manner in Drosophila. To identify central regulators of protein aggregation, we further generated stable Drosophila cell lines expressing these Htt mutants and also established a cell-based quantitative assay that allows automated measurement of aggregates within cells. We then performed a genomewide RNA interference screen for regulators of mutant Htt aggregation and isolated 126 genes involved in diverse cellular processes. Interestingly, although our screen focused only on mutant Htt aggregation, several of the identified candidates were known previously as toxicity modifiers of NDs. Moreover, modulating the in vivo activity of hsp110 (CG6603) or tra1, two hits from the screen, affects neurodegeneration in a dose-dependent manner in a Drosophila model of Huntington's disease. Thus, other aggregates regulators isolated in our screen may identify additional genes involved in the proteinfolding pathway and neurotoxicity.

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Section: Resultsmentioning

confidence: 99%

A Genomewide RNA Interference Screen for Modifiers of Aggregates Formation by Mutant Huntingtin in Drosophila

Zhang¹,

Binari

Zhou³

et al. 2010

Genetics

146

176

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“…The level of Boss protein detectable in R7 cells is sensitive to mutations that perturb endocytic trafficking (Chang et al, 2002;Sevrioukov et al, 1999;Sunio et al, 1999). After dVps16A knockdown using the da-Gal4 driver, the level of Boss expressed on the R8 cell surface was not significantly altered, indicating no change in secretion.…”

Section: Identification Of Two Drosophila Vps16 Homologsmentioning

confidence: 92%

DrosophilaVps16A is required for trafficking to lysosomes and biogenesis of pigment granules

Pulipparacharuvil

Akbar²,

Ray

et al. 2005

Journal of Cell Science

225

288

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Mutations that disrupt trafficking to lysosomes and lysosome-related organelles cause multiple diseases, including Hermansky-Pudlak syndrome. The Drosophila eye is a model system for analyzing such mutations. The eye-color genes carnation and deep orange encode two subunits of the Vps-C protein complex required for endosomal trafficking and pigment-granule biogenesis. Here we demonstrate that dVps16A (CG8454) encodes another Vps-C subunit. Biochemical experiments revealed a specific interaction between the dVps16A C-terminus and the Sec1/Munc18 homolog Carnation but not its closest homolog, dVps33B. Instead, dVps33B interacted with a related protein, dVps16B (CG18112). Deep orange bound both Vps16 homologs. Like a deep orange null mutation, eye-specific RNAi-induced knockdown of dVps16A inhibited lysosomal delivery of internalized ligands and interfered with biogenesis of pigment granules. Ubiquitous knockdown of dVps16A was lethal. Together, these findings demonstrate that Drosophila Vps16A is essential for lysosomal trafficking. Furthermore, metazoans have two types of Vps-C complexes with non-redundant functions.

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“…The Hsp70 cognate, Hsc70-4, binds to clathrin and dynamin and participates in the assembly and disassembly of clathrin cages, with mutants showing defects in endocytosis and exocytosis (Schlossman et al 1984;Bronk et al 2001;Newmyer and Schmid 2001;Chang et al 2002;Newmyer et al 2003). In Hsp70 1 flies, perhaps Hsp70 takes the part of Hsc70-4 and associates with clathrin and/or dynamin at high temperature.…”

Section: Discussionmentioning

confidence: 99%

Loss of Hsp70 in Drosophila Is Pleiotropic, With Effects on Thermotolerance, Recovery From Heat Shock and Neurodegeneration

Gong

Golic²

2006

Genetics

128

106

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The heat-shock response is a programmed change in gene expression carried out by cells in response to environmental stress, such as heat. This response is universal and is characterized by the synthesis of a small group of conserved protein chaperones. In Drosophila melanogaster the Hsp70 chaperone dominates the profile of protein synthesis during the heat-shock response. We recently generated precise deletion alleles of the Hsp70 genes of D. melanogaster and have used those alleles to characterize the phenotypes of Hsp70-deficient flies. Flies with Hsp70 deletions have reduced thermotolerance. We find that Hsp70 is essential to survive a severe heat shock, but is not required to survive a milder heat shock, indicating that a significant degree of thermotolerance remains in the absence of Hsp70. However, flies without Hsp70 have a lengthened heat-shock response and an extended developmental delay after a non-lethal heat shock, indicating Hsp70 has an important role in recovery from stress, even at lower temperatures. Lack of Hsp70 also confers enhanced sensitivity to a temperature-sensitive lethal mutation and to the neurodegenerative effects produced by expression of a human polyglutamine disease protein.

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Hsc70 is required for endocytosis and clathrin function in Drosophila

Cited by 121 publications

References 56 publications

A Genomewide RNA Interference Screen for Modifiers of Aggregates Formation by Mutant Huntingtin in Drosophila

A Genomewide RNA Interference Screen for Modifiers of Aggregates Formation by Mutant Huntingtin in Drosophila

DrosophilaVps16A is required for trafficking to lysosomes and biogenesis of pigment granules

Loss of Hsp70 in Drosophila Is Pleiotropic, With Effects on Thermotolerance, Recovery From Heat Shock and Neurodegeneration

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