Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease

Ju, Jeong-Sun; Fuentealba, Rodrigo A.; Miller, Sara; Jackson, Erin; Piwnica-Worms, David; Baloh, Robert H.; Weihl, Conrad C.

doi:10.1083/jcb.200908115

Cited by 461 publications

(488 citation statements)

References 51 publications

Supporting

Mentioning

465

Contrasting

Unclassified

Order By: Relevance

“…In a control situation, ammonium chloride treatment leads to the accumulation of Lc3-II proteins due to the blockade of the lysosomal degradation of Lc3-II. Interestingly, we did not find significantly elevated Lc3-II levels in ammonium chloride treated MO- vcp -injected zebrafish embryos compared to DMSO-treated Vcp morphants, clearly demonstrating that, similar to the situation in HeLa cells and mice devoid of functional VCP [27], autophagic flux and thereby autophagic function is also impaired in Vcp-deficient zebrafish embryos. To further substantiate this finding, we assessed the impact of Vcp deficiency on the function of the autophagy system using a therefore generated novel striated muscle-specific transgenic autophagy-reporter zebrafish line Tg(unc45b:mCherry-EGFP-LC3B) and found, similar to the Lc3-II western blot analyses, impaired autophagic flux in Vcp-deficient zebrafish muscle in vivo .…”

Section: Discussionsupporting

confidence: 58%

“…Recently, VCP was demonstrated to be also involved in autophagic degradation of ubiquitinated substrates [26,27]. To evaluate whether autophagy-mediated protein degradation, similar to UPS-mediated degradation, is impaired by the loss of Vcp in vivo , we assessed protein levels of Sqstm1/p62 (sequestosome 1) and Lc3A/B-II, the lipidated and autophagosome-associated form of Lc3A/B or Map1lc3A/B (microtubule-associated protein 1 light chain 3) (hereafter referred to as Lc3), 2 established markers of autophagy function [28].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

et al. 2018

View full text Add to dashboard Cite

VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We found that targeted inactivation of either Vcp or Washc4, led to progressive impairment of cardiac and skeletal muscle function, structure and cytoarchitecture without interfering with the differentiation of both organ systems. Notably, loss of Vcp resulted in compromised protein degradation via the proteasome and the macroautophagy/autophagy machinery, whereas Washc4 deficiency did not affect the function of the ubiquitin-proteasome system (UPS) but caused ER stress and interfered with autophagy function in vivo. In summary, our findings provide novel insights into the in vivo functions of Vcp and its novel interactor Washc4 and their particular and distinct roles during proteostasis in striated muscle cells.

show abstract

Section: Discussionsupporting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

et al. 2018

View full text Add to dashboard Cite

show abstract

“…When viral degradation is blocked by VCP inhibition within the first few hours post infection, productive infection proceeds. A number of recent studies have shown that VCP is also required for autophagy (32,33), with the exact mechanism still subject of debate (34). Although depleting or inhibiting VCP is, thus, bound to impact this process, we consider impairment of autophagy unlikely to underlie the requirement for VCP in ADIN, since specific inhibition of the proteasome abrogates intracellular neutralization entirely [ Fig.…”

Section: Discussionmentioning

confidence: 99%

AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization

Hauler

Mallery

McEwan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Tripartite motif-containing 21 (TRIM21) is a cytosolic IgG receptor that mediates intracellular virus neutralization by antibody. TRIM21 targets virions for destruction in the proteasome, but it is unclear how a substrate as large as a viral capsid is degraded. Here, we identify the ATPase p97/valosin-containing protein (VCP), an enzyme with segregase and unfoldase activity, as a key player in this process. Depletion or catalytic inhibition of VCP prevents capsid degradation and reduces neutralization. VCP is required concurrently with the proteasome, as addition of inhibitor after proteasomal degradation has no effect. Moreover, our results suggest that it is the challenging nature of virus as a substrate that necessitates involvement of VCP, since intracellularly expressed IgG Fc is degraded in a VCP-independent manner. These results implicate VCP as an important host factor in antiviral immunity.A ntibody neutralization is a key component of the antiviral response and provides protective immunity. Our recent work has shown that neutralization can occur inside cells, in an effector-driven process mediated by tripartite motif-containing 21 (TRIM21). TRIM21, a cytosolic antibody receptor of ultrahigh affinity to IgG Fc (1, 2), is recruited to antibody-bound virus and targets the complex to the proteasome for degradation (3). This process potently neutralizes viral infection and has been termed antibody-dependent intracellular neutralization (ADIN) (4). ADIN is dependent upon the E3 ubiquitin ligase activity of TRIM21 and can be abrogated by chemical inhibition of the proteasome.Although both proteasomal activity and ubiquitination are necessary for ADIN, the exact mechanism of virus degradation is poorly understood. Specifically, it is not clear how the proteasome can degrade a virion, a compact proteinaceous particle much larger than the proteasome itself. The 26S proteasome has a mass of ∼2.5 MDa (5), and the pore through which substrates must pass to access the proteolytic chamber is no greater than 2 nm in diameter (6, 7). In contrast, human adenovirus (AdV), a virus potently neutralized by TRIM21, has a diameter of ∼100 nm and a mass of 150 MDa (8).Although there are ATPases in the 19S regulatory subunit of the 26S proteasome that may unfold substrates and allow them to enter through the pore (5, 6), AdV virions are much larger than any of the proteasome's known cellular substrates. Because ADIN has been shown to be independent of autophagy but dependent on proteasomal degradation (3), we hypothesized that an additional energydependent step of AdV capsid disassembly and/or unfolding might precede proteasomal degradation of the virus.In recent studies, the ATPase p97/VCP of the AAA (ATPases associated with diverse cellular activities) family has been implicated in the proteasomal degradation of certain cytosolic substrates (9-13). VCP is capable of dissociating proteins from large cellular structures such as the endoplasmic reticulum (14), the mitotic spindle (12), the nuclear envelope (15), and chromatin (1...

show abstract

“…On the cellular level, both diseases are characterized by cytoplasmic protein inclusions (aggregates) positive for ubiquitin and the Tar DNA-binding Protein 43 . Analysis of IBMPFD patient-derived cell-lines and IBMPFD mouse models revealed that disease-causing point mutations in VCP affect autophagy and endolysosomal protein degradation [9,10].…”

Section: Introductionmentioning

confidence: 99%

Control of p97 function by cofactor binding

2015

View full text Add to dashboard Cite

Edited by Wilhelm JustKeywords: ATPases Associated with diverse cellular Activities p47 UFD1-NPL4 UBXD1 Inclusion Body Myopathy with Pagets disease of the bone and Fronto-temporal Dementia a b s t r a c t p97 (also known as Cdc48, Ter94, and VCP) is an essential, abundant and highly conserved ATPase driving the turnover of ubiquitylated proteins in eukaryotes. Even though p97 is involved in highly diverse cellular pathways and processes, it exhibits hardly any substrate specificity on its own. Instead, it relies on a large number of regulatory cofactors controlling substrate specificity and turnover. The complexity as well as temporal and spatial regulation of the interactions between p97 and its cofactors is only beginning to be understood at the molecular level. Here, we give an overview on the structural framework of p97 interactions with its cofactors, the emerging principles underlying the assembly of complexes with different cofactors, and the pathogenic effects of disease-associated p97 mutations on cofactor binding.

show abstract

Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease

Abstract: Accumulation of autophagosomes because of impaired autophagy during valosin-containing protein (VCP)–linked dementia is explained by the absence or reduced activity of VCP.

Cited by 461 publications

References 51 publications

Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization

Control of p97 function by cofactor binding

Contact Info

Product

Resources

About