p47 is a cofactor for p97-mediated membrane fusion

Kondo, Hisao; Rabouille, Cathérine; Newman, Richard; Levine, Tim P.; Pappin, Darryl; Freemont, Paul S.; Warren, Graham

doi:10.1038/40411

Cited by 411 publications

(427 citation statements)

References 25 publications

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“…Here, we only identified RNA binding protein FUS (FUS) and PTBP1 cleaved at the same site as found before, strongly suggesting the involvement of Substrate degradomics of taxol-treated A549 cells F Impens et al Substrate degradomics of taxol-treated A549 cells F Impens et al caspases. Two further interesting substrates are NSFL1/ p47 and reticulon-4 (Nogo), both associated with membranes or membrane proteins (Kondo et al, 1997;Yan et al, 2006) and whose cleavage could be in line with the lysosomal permeability observed after taxol treatment. Overall, our substrate list may be the source for future experiments in which some of the hypotheses forwarded here could be verified.…”

Section: Discussionmentioning

confidence: 95%

Mechanistic insight into taxol-induced cell death

et al. 2008

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We analysed the involvement of proteases during taxolmediated cell death of human A549 non-small-cell lung carcinoma cells using a proteomics approach that specifically targets protein N termini and further detects newly formed N termini that are the result of protein processing. Our analysis revealed 27 protease-mediated cleavages, which we divided in sites C-terminal to aspartic acid (Asp) and sites C-terminal to non-Asp residues, as the result of caspase and non-caspase protease activities, respectively. Remarkably, some of the former were insensitive to potent pancaspase inhibitors, and we therefore suggest that previous inhibitor-based studies that report on the caspaseindependent nature of taxol-induced cell death should be judged with care. Furthermore, many of the sites C-terminal to non-Asp residues were also uniquely observed in a model of cytotoxic granule-mediated cell death and/or found by in vitro cataloging human l-calpain substrates using a similar proteomics technique. This thus raises the hypothesis that killing tumor cells by chemotherapy or by immune cells holds similar non-Asp-specific proteolytic components with strong indications to calpain activity.

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Section: Discussionmentioning

confidence: 95%

Mechanistic insight into taxol-induced cell death

et al. 2008

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“…Bar, 100 nm. cisternae in vitro, NSF (and its cofactor ␣SNAP), and p97 (and its cofactor p47) (Acharya et al, 1995;Rabouille et al, 1995a;Kondo et al, 1997). We tested the involvement of dNSF1 (one of the two Drosophila homologs of mammalian NSF) in the observed Golgi stack biogenesis with the use of larvae from comt 17 homozygote stocks (gifts from Dr. B. Ganetsky).…”

Section: Dnsf1 and Formation Of Golgi Stacksmentioning

confidence: 99%

“…The semi-intact cell system visualized the rebuilding of the Golgi complex from illimaquinone-generated Golgi fragments (Acharya et al, 1995). These assays have allowed the identification of several proteins involved in this rebuilding process, such as NEM sensitive factor (NSF) and its cofactor ␣ soluble NSF attachment protein (a-SNAP) (Acharya et al, 1995;Rabouille et al, 1995a;Mü ller et al, 1999), p97 (Acharya et al, 1995;Rabouille et al, 1995a), and its cofactor p47 (Kondo et al, 1997). Syntaxin 5 was shown to interact with both fusion machineries .…”

Section: Introductionmentioning

confidence: 99%

Biogenesis of Golgi Stacks in Imaginal Discs ofDrosophila melanogaster

Kondylis

Goulding

Dunne

et al. 2001

MBoC

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We provide a detailed description of Golgi stack biogenesis that takes place in vivo during one of the morphogenetic events in the lifespan of Drosophila melanogaster. In early third-instar larvae, small clusters consisting mostly of vesicles and tubules were present in epithelial imaginal disk cells. As larvae progressed through mid-and late-third instar, these larval clusters became larger but also increasingly formed cisternae, some of which were stacked. In white pupae, the typical Golgi stack was observed. We show that larval clusters are Golgi stack precursors by 1) localizing various Golgi-specific markers to the larval clusters by electron and immunofluorescence confocal microscopy, 2) driving this conversion in wild-type larvae incubated at 37°C for 2 h, and 3) showing that this conversion does not take place in an NSF1 mutant (comt 17). The biological significance of this conversion became clear when we found that the steroid hormone 20-hydroxyecdysone (ecdysone) is critically involved in this conversion. In its absence, Golgi stack biogenesis did not occur and the larval clusters remained unaltered. We showed that dGM130 and sec23p expression increases approximately three-and fivefold, respectively, when discs are exposed to ecdysone in vivo and in vitro. Taken together, these results suggest that we have developed an in vivo system to study the ecdysone-triggered Golgi stack biogenesis.

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“…To date, a large number of p97 cofactors have been identified [32]. Among them, the best-characterized ones are a dimeric complex comprising Ufd1 and Npl4 [33], which assists p97 in degradation of misfolded ER proteins [34], and p47, which facilitates p97 function in homotypic fusion of Golgi membranes [35]. We tested whether these p97 cofactors were involved in EEA1-p97 interaction.…”

Section: The P97 Is Localized To the Endosomes And Interacts With Eea1mentioning

confidence: 99%

The p97 ATPase associates with EEA1 to regulate the size of early endosomes

Ramanathan

2011

Cell Res

100

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The AAA (ATPase-associated with various cellular activities) ATPase p97 acts on diverse substrate proteins to partake in various cellular processes such as membrane fusion and endoplasmic reticulum-associated degradation (ERAD). In membrane fusion, p97 is thought to function in analogy to the related ATPase NSF (N-ethylmaleimidesensitive fusion protein), which promotes membrane fusion by disassembling a SNARE complex. In ERAD, p97 dislocates misfolded proteins from the ER membrane to facilitate their turnover by the proteasome. Here, we identify a novel function of p97 in endocytic trafficking by establishing the early endosomal autoantigen 1 (EEA1) as a new p97 substrate. We demonstrate that a fraction of p97 is localized to the early endosome membrane, where it binds EEA1 via the N-terminal C2H2 zinc finger domain. Inhibition of p97 either by siRNA or a pharmacological inhibitor results in clustering and enlargement of early endosomes, which is associated with an altered trafficking pattern for an endocytic cargo. Mechanistically, we show that p97 inhibition causes increased EEA1 self-association at the endosome membrane. We propose that p97 may regulate the size of early endosomes by governing the oligomeric state of EEA1.

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p47 is a cofactor for p97-mediated membrane fusion

Cited by 411 publications

References 25 publications

Mechanistic insight into taxol-induced cell death

Mechanistic insight into taxol-induced cell death

Biogenesis of Golgi Stacks in Imaginal Discs ofDrosophila melanogaster

The p97 ATPase associates with EEA1 to regulate the size of early endosomes

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