VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD

Tresse, Emilie; Salomons, Florian A.; Vesa, Jouni; Bott, Laura C.; Kimonis, Virginia; Yao, Tso‐Pang; Dantuma, Nico P.; Taylor, J. Paul

doi:10.4161/auto.6.2.11014

Cited by 405 publications

(386 citation statements)

References 39 publications

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“…This suggestion is supported by reports showing that the histone deacetylase HDAC6 and VCP/p97 (valosin-containing protein) are needed for the clearance of basal, but not starvation-induced, autophagosomes. 33,34 Interestingly, our results showed that in the absence of RAB24, autophagosome clearance was not efficient in full-culture medium, but on the contrary, autophagosomes were cleared in full-culture medium if they were first induced by amino acid deprivation. This result suggests that the autophagosomes formed under amino acid deficiency and full culture medium conditions are somehow different, or that partly different molecular machineries are at work when these 2 autophagosome populations are cleared.…”

Section: Discussionmentioning

confidence: 70%

RAB24 facilitates clearance of autophagic compartments during basal conditions

et al. 2015

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RAB24 belongs to a family of small GTPases and has been implicated to function in autophagy. Here we confirm the intracellular localization of RAB24 to autophagic vacuoles with immuno electron microscopy and cell fractionation, and show that prenylation and guanine nucleotide binding are necessary for the targeting of RAB24 to autophagic compartments. Further, we show that RAB24 plays a role in the maturation and/or clearance of autophagic compartments under nutrient-rich conditions, but not during short amino acid starvation. Quantitative electron microscopy shows an increase in the numbers of late autophagic compartments in cells silenced for RAB24, and mRFP-GFP-LC3 probe and autophagy flux experiments indicate that this is due to a hindrance in their clearance. Formation of autophagosomes is shown to be unaffected by RAB24-silencing with siRNA. A defect in aggregate clearance in the absence of RAB24 is also shown in cells forming polyglutamine aggregates. This study places RAB24 function in the termination of the autophagic process under nutrient-rich conditions.

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Section: Discussionmentioning

confidence: 70%

RAB24 facilitates clearance of autophagic compartments during basal conditions

et al. 2015

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“…Since interactions between VCP and substrates are often transient and difficult to detect, we used a catalytically dead mutant form of VCP (VCP‐DKO) in addition to wild‐type VCP. With mutations in both ATPase domains (E305Q/E578Q), VCP‐DKO cannot process and thus traps its substrates (Dalal et al , 2004; Tresse et al , 2010). Pull‐down analysis of the GFP‐tagged VCP variants revealed that both unmodified and ubiquitinated Evi interacted with catalytically inactive VCP‐DKO (Fig 5B, lanes 5 and 6), affirming that Evi is a VCP client.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to Evi, N‐cadherin did not interact with VCP‐DKO, confirming specificity of the Evi‐VCP‐DKO interaction (Fig EV4B). VCP‐DKO forms hexamers with endogenous VCP and thereby disrupts endogenous VCP activity (Tresse et al , 2010). Consistently, the ubiquitination and steady‐state level of Evi were increased upon overexpression of VCP‐DKO (Fig 5B, lanes 5 and 6), further providing evidence that Evi is a VCP client.…”

Section: Resultsmentioning

confidence: 99%

“…Cells were harvested 48 h after transfection. The following expression constructs were used: pSpCas9(BB)‐2A‐Puro (px459; Addgene #48139; Ran et al , 2013), psPAX2 (Addgene #12260; D. Trono), pMD2.G‐VSVG (Addgene #12259; D. Trono), TCF4/Wnt‐Firefly Luciferase (Demir et al , 2013), Actin‐Renilla Luciferase (Nickles et al , 2012), pcDNA3‐Wnt11 (Addgene #35922; Najdi et al , 2012), pcDNA3‐Wnt10B, (Addgene #35921; Najdi et al , 2012), pcDNA3‐Wnt16 (Addgene #35923; Najdi et al , 2012), pcDNA3‐Wnt7B (Addgene #35915; Najdi et al , 2012), pcDNA3‐Wnt8 (Addgene #35916; Najdi et al , 2012), pcDNA3‐Wnt5A (Addgene #35911; Najdi et al , 2012), pcDNA3‐Wnt3A (Addgene #35908; Najdi et al , 2012), pcDNA3‐Wnt3 (Addgene #35909; Najdi et al , 2012), pcDNA3.2‐Wnt3A‐V5 (Addgene #43810; MacDonald et al , 2014), pcDNA3‐IGFBP5‐V5 (Addgene #11608; S. Johnson), pcDNA3‐EGF‐Myc (Addgene #11601; Nguyen et al , 2000), VCP(wt)‐EGFP (Addgene #23971; Tresse et al , 2010), VCP(DKO)‐EGFP (Addgene #23974; Tresse et al , 2010), pCMV6‐Myc‐DDK‐tagged PORCN (Origene # RC223764), sLuc (Katanaev et al , 2008), pCS2(+)‐mWnt3A (C. Niehrs), pCS2(+)‐Dvl3 (C. Niehrs), pCS2(+)‐mWnt3A‐S209A (Kumar et al , 2014), and β‐Catenin‐YFP (Stemmer et al , 2008). To generate C‐terminally FLAG‐HA‐tagged CGRRF1 and Hrd1, the FLAG‐HA sequence was inserted into the pcDNA5‐FRT/TO vector (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

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ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β‐catenin by the ubiquitin‐proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)‐associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP‐dependent manner. Ubiquitination of Evi involves the E2‐conjugating enzyme UBE2J2 and the E3‐ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD‐dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

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“…In physiologic macroautophagy, the delivery of autophagosome to lysosomes, in order to form an autolysosome, depends on microtubules in a dynein/ dynactin-dependent manner (Mizushima, 2007). In the vacuolar membranes of ALS tissues an abnormal accumulation of lysosome-associated membrane proteins (LAMP-1 and LAMP-2) and LC3-I, which are the major protein markers of autophagosome, was observed, suggesting that immature autophagosomes could be the result of an alteration in the final fusion steps between autophagosomes and lysosomes (Tresse et al, 2010). Impairment of the retrograde axonal transport in SOD1 G93A mice may be responsible for the accumulation of autophagosomes as a result of a defect in the autophagosome-lysosome fusion, which occurs mainly in the soma (Nixon, 2007).…”

Section: The Autophagic Processes In Healthy and Als Contextmentioning

confidence: 99%

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

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a b s t r a c tAutophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases..

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VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD

Cited by 405 publications

References 39 publications

RAB24 facilitates clearance of autophagic compartments during basal conditions

RAB24 facilitates clearance of autophagic compartments during basal conditions

ERAD‐dependent control of the Wnt secretory factor Evi

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

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