A complex of mammalian Ufd1 and Npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways

Meyer, Hemmo; Shorter, James; Seemann, Joachim; Pappin, Darryl; Warren, Graham

doi:10.1093/emboj/19.10.2181

Cited by 421 publications

(419 citation statements)

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“…76,77 Ubiquitination machinery similar to that of yeast is also employed, and a homolog of Cdc48p, termed p97, has been shown to cooperate with mammalian homologs of Ufd1p and Npl4p in substrate dislocation. [78][79][80] Recently, two groups using independent functional criteria identified Derlin1 as a mammalian homolog of Der1p and demonstrated that it mediates the association of p97 with the ER membrane to facilitate ERAD. 81,82 Another protein in this p97 targeting complex, VIMP, was also identified in one of these studies.…”

Section: Esr In Mammalsmentioning

confidence: 99%

Cellular response to endoplasmic reticulum stress: a matter of life or death

2006

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The proper functioning of the endoplasmic reticulum (ER) is critical for numerous aspects of cell physiology. Accordingly, all eukaryotes react rapidly to ER dysfunction through a set of adaptive pathways known collectively as the ER stress response (ESR). Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger programmed cell death, or apoptosis. ER stress and the apoptotic program coupled to it have been implicated in many important pathologies but the regulation and execution of ER stressinduced apoptosis in mammals remain incompletely understood. Here, we review what is known about the ESR in both yeast and mammals, and highlight recent findings on the mechanism and pathophysiological importance of ER stressinduced apoptosis.

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Section: Esr In Mammalsmentioning

confidence: 99%

Cellular response to endoplasmic reticulum stress: a matter of life or death

2006

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“…Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc. E03-02-0097.1997), Ufd1/Npl4 (Meyer et al, 2000(Meyer et al, , 2002, VCIP135 (Uchiyama et al, 2002), and SVIP (Nagahama et al, 2003).…”

Section: Introductionmentioning

confidence: 98%

“…These include roles in ubiquitin-and proteasome-dependent degradation of cytosolic proteins (Ghislain et al, 1996;Dai et al, 1998;Dai and Li, 2001), ER-associated degradation (ERAD; reviewed in Bays and Hampton, 2002;Tsai et al, 2002), and regulated ubiquitindependent processing (Rape et al, 2001 1997), Ufd1/Npl4 (Meyer et al, 2000(Meyer et al, , 2002, VCIP135 (Uchiyama et al, 2002), and SVIP (Nagahama et al, 2003). Although the mechanism by which AAA ATPases such as NSF and p97 use ATP to modulate the structure of their substrates is not known, the overall homology between these two enzymes makes the idea that they might operate by a similar mechanism attractive.…”

Section: Introductionmentioning

confidence: 99%

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Distinct Roles for the AAA ATPases NSF and p97 in the Secretory Pathway

Dalal

Rosser

Cyr

et al. 2004

MBoC

166

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NSF and p97 are related AAA proteins implicated in membrane trafficking and organelle biogenesis. p97 is also involved in pathways that lead to ubiquitin-dependent proteolysis, including ER-associated degradation (ERAD). In this study, we have used dominant interfering ATP-hydrolysis deficient mutants (NSF(E329Q) and p97(E578Q)) to compare the function of these AAA proteins in the secretory pathway of mammalian cells. Expressing NSF(E329Q) promotes disassembly of Golgi stacks into dispersed vesicular structures. It also rapidly inhibits glycosaminoglycan sulfation, reflecting disruption of intra-Golgi transport. In contrast, expressing p97(E578Q) does not affect Golgi structure or function; glycosaminoglycans are normally sulfated and secreted, as is the VSV-G ts045 protein. Instead, expression of p97(E578Q) causes ubiquitinated proteins to accumulate on ER membranes and slows degradation of the ERAD substrate cystic-fibrosis transmembrane-conductance regulator. In addition, expression of p97(E578Q) eventually causes the ER to swell. More specific assessment of effects of p97(E578Q) on organelle assembly shows that the Golgi apparatus disperses and reassembles normally after treatment with brefeldin A and during mitosis. These findings demonstrate that ATPhydrolysis-dependent activities of NSF and p97 in the cell are not equivalent and suggest that only NSF is directly involved in regulating membrane fusion. INTRODUCTIONMembrane fusion is an essential step in all forms of vesicle trafficking and organelle assembly. Fusion is driven by a series of regulated protein-protein interactions. Many participating proteins have been identified, and their specific roles are gradually coming to light (reviewed in Jahn et al., 2003). Among these proteins are a number of ATPases.N-ethyl maleimide sensitive factor (NSF) was one of the first proteins specifically linked to membrane fusion (Wilson et al., 1989). It belongs to a family of chaperone-like ATPases known as AAA (ATPases associated with a variety of cellular activities) proteins (Neuwald et al., 1999). NSF together with ␣-SNAP (soluble NSF attachment protein) dissociates the SNARE (SNAP receptor) complexes that promote association and fusion of cellular membranes. More recently, NSF has also been implicated in other cellular processes on the basis of its ability to bind the AMPA receptor GluR2, ␤-arrestin 1, and GATE-16 (reviewed in Whiteheart et al., 2001). However, its role in SNARE disassembly and membrane fusion remains its best understood function.Not all ATP-requiring steps that lead to membrane fusion can be attributed to NSF (Goda and Pfeffer, 1991;Latterich and Schekman, 1994;Rodriguez et al., 1994;Wilson, 1995).Other ATPases must therefore be involved. One AAA protein thought to be an alternate to NSF is known as p97 (also referred to as valosin-containing protein, VCP). p97 is an abundant and highly conserved protein (Peters et al., 1990) whose cellular function has been the subject of much debate. A break in the mystery of p97's function came when it turn...

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“…VCP has been associated with several essential cell protein pathways 11 : cell cycle, homotypic membrane fusion, nuclear envelope reconstruction, postmitotic Golgi reassembly, DNA damage response, suppressor of apoptosis and ubiquitin-dependent protein degradation [12][13][14][15][16][17][18] . VCP also binds to expanded polyglutamine (poly-Q) protein aggregates 18,19 .…”

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confidence: 99%

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

et al. 2004

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Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1-p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosincontaining protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in ~50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.Hereditary inclusion body myopathy (IBM) associated with PDB and frontotemporal dementia (FTD), or IBMPFD, is a rare, complex and ultimately lethal autosomal dominant disorder (OMIM 605382; ref. 1). IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset PDB in most cases and 'premature' FTD 2 . Although the disorder was mapped to chromosome 9p21-p12, the genetic basis was not known.Within 13 families (12 from the United States and 1 from Canada, Fig. 1 and Supplementary Fig. 1 online), 82% of individuals had myopathy, 49% had PDB and 30% had early-onset FTD. The mean age of presentation was 42 years for both IBM and PDB, whereas FTD typically presented at age 53 years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear similar, suggestive of disruptions in the same pathological pathway.Haplotype analysis of the families with IBMPFD identified two ancestral, disease-associated haplotypes, distinguishing families 1, 3, 7 and 16 (group A) from families 2 and 5 (group B), both groups of Northern European ancestry ( Table 1

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A complex of mammalian Ufd1 and Npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways

Cited by 421 publications

References 45 publications

Cellular response to endoplasmic reticulum stress: a matter of life or death

Cellular response to endoplasmic reticulum stress: a matter of life or death

Distinct Roles for the AAA ATPases NSF and p97 in the Secretory Pathway

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

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