Analysis of the two p97/VCP/Cdc48p proteins of Caenorhabditis elegans and their suppression of polyglutamine-induced protein aggregation

Yamanaka, Kunitoshi; Okubo, Yoshiyuki; Suzaki, Toshinobu; Ogura, Teru

doi:10.1016/j.jsb.2003.11.017

Cited by 63 publications

(64 citation statements)

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“…As described above, in the cdc-48.1(tm544) mutant, an embryonic-lethal phenotype and developmental defects were not observed except for the slight reduction in growth rate. (Yamanaka et al, 2004) and that the amount of CDC-48.1 is almost double that of CDC-48.2 in C. elegans (Yamauchi et al, 2006). Therefore, the cdc-48.2(tm659) mutant would still contain enough CDC-48/p97 to maintain the normal brood size at 20°C.…”

Section: Resultsmentioning

confidence: 99%

“…Reduced brood size in cdc-48.1 mutant worms We have previously reported that C. elegans possesses two p97 homologues, namely, CDC-48.1 and CDC-48.2, which are essential for embryogenesis, meiosis, ERAD and germline development (Yamanaka et al, 2004;Sasagawa et al, 2007b;Sasagawa et al, 2007c). The protein levels and expression patterns of these two p97 homologues are differentially regulated (Yamauchi et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

“…By contrast, C. elegans possesses two genescdc-48.1(C06A1.1) and cdc-48.2(C41C4.8) -encoding p97 with 88% identity over the entire protein (Yamanaka et al, 2004). We have previously reported that both homologues are essential in C. elegans and that their cellular functions are redundant (Yamanaka et al, 2004;Sasagawa et al, 2007b;Sasagawa et al, 2007c).…”

Section: Introductionmentioning

confidence: 99%

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Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner

Sasagawa

Otani

Higashitani

et al. 2009

Journal of Cell Science

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p97 (CDC-48 inCaenorhabditis elegans) is a ubiquitin-selective AAA (ATPases associated with diverse cellular activities) chaperone and its key function is to disassemble protein complexes. p97 functions in diverse cellular processes including endoplasmic reticulum (ER)-associated degradation, membrane fusion, and meiotic and mitotic progression. However, its cellular functions in development have not yet been clarified. Here, we present data that p97 is involved in the switch from spermatogenesis to oogenesis in the germline of the C. elegans hermaphrodite. We found that the cdc-48.1 deletion mutant produced less sperm than the wild type and thus showed a decreased brood size. The cdc-48.1 mutation suppressed the sperm-overproducing phenotypes of fbf-1 and fem-3(gf) mutants. In addition, the p97/CDC-48-UFD-1-NPL-4 complex interacted with the E3 ubiquitin ligase CUL-2 complex via NPL-4 binding to Elongin C. Furthermore, TRA-1A, which is the terminal effector of the sex determination pathway and is regulated by CUL-2-mediated proteolysis, accumulated in the cdc-48.1 mutant. Proteasome activity was also required for the brood size determination and sperm-oocyte switch. Our results demonstrate that the C. elegans p97/CDC-48-UFD-1-NPL-4 complex controls the sperm-oocyte switch by regulating CUL-2-mediated TRA-1A proteasome degradation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner

Sasagawa

Otani

Higashitani

et al. 2009

Journal of Cell Science

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“…Unfortunately, VCP knockout mice are not available to test the hypothesis and a more complex strategy may be needed. Given the essential role of VCP in endoplasmic reticulumassociated protein degradation (ERAD) and several reports of damaging effects of VCP RNAi, mutation, and deletion in other species or cell lines, it is unlikely that such knockout mice would be viable (Hirabayashi et al, 2001;Kobayashi et al, 2002;Wojcik et al, 2004;Yamanaka et al, 2004). In contrast, Wld S alters VCP in a way that leaves all cells and organisms healthy, with no overt harmful effect in the orig- S /EGFP localizes primarily to discrete intranuclear foci (arrowhead), although some remains homogeneously distributed inside the nucleus (arrow).…”

Section: Discussionmentioning

confidence: 99%

The Slow Wallerian Degeneration Protein, Wld^S, Binds Directly to VCP/p97 and Partially Redistributes It within the Nucleus

Laser

Conforti

Morreale

et al. 2006

MBoC

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Slow Wallerian degeneration (Wld S ) mutant mice express a chimeric nuclear protein that protects sick or injured axons from degeneration. The C-terminal region, derived from NAD؉ synthesizing enzyme Nmnat1, is reported to confer neuroprotection in vitro. However, an additional role for the N-terminal 70 amino acids (N70), derived from multiubiquitination factor Ube4b, has not been excluded. In wild-type Ube4b, N70 is part of a sequence essential for ubiquitination activity but its role is not understood. We report direct binding of N70 to valosin-containing protein (VCP; p97/Cdc48), a protein with diverse cellular roles including a pivotal role in the ubiquitin proteasome system. Interaction with Wld S targets VCP to discrete intranuclear foci where ubiquitin epitopes can also accumulate. Wld S lacking its N-terminal 16 amino acids (N16) neither binds nor redistributes VCP, but continues to accumulate in intranuclear foci, targeting its intrinsic NAD ؉ synthesis activity to these same foci. Wild-type Ube4b also requires N16 to bind VCP, despite a more C-terminal binding site in invertebrate orthologues. We conclude that N-terminal sequences of Wld S protein influence the intranuclear location of both ubiquitin proteasome and NAD ؉ synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP. INTRODUCTIONThe E4 ubiquitination factor Ube4b (or Ufd2a) has a 123-amino acid N-terminal region that is essential for ubiquitination activity (Mahoney et al., 2002). It is unclear why this region is essential because it does not contain the U box, and it appears to be absent in invertebrate orthologues that ubiquitinate effectively (Koegl et al., 1999;Hatakeyama et al., 2001;Mahoney et al., 2002;Hoppe et al., 2004;Richly et al., 2005). It is important to understand the molecular mechanism of Ube4b because it has a key role in the ubiquitin proteasome system (UPS; Hoppe, 2005), it is neuroprotective in polyglutamine disorders and an important candidate gene for neuroblastoma (Krona et al., 2003). Information on the substrates of Ube4b is beginning to emerge (Hoppe et al., 2004;Okumura et al., 2004;Spinette et al., 2004;Richly et al., 2005) but there is much still to learn about its regulation.In the slow Wallerian degeneration mutant mouse (Wld S ), 70 amino acids of this essential domain of Ube4b form the N-terminus of a chimeric protein that delays Wallerian degeneration of injured axons in mice and rats by 10-fold (see Figure 1A; Lunn et al., 1989;Mack et al., 2001;Adalbert et al., 2005). The chimeric protein is absent in wild-type mice. This sequence (N70) is fused in Wld S protein to the full coding sequence of nicotinamide mononucleotide adenylyltransferase (Nmnat1; Conforti et al., 2000;Emanuelli et al., 2001;Mack et al., 2001) in regulating axon degeneration. Wld S also delays axon degeneration in a wide range of neurodegenerative disorders and acute retrograde axonal degeneration after spinal injury, indicating that axon degeneration mechanisms are more closely related th...

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“…This was recently confirmed by electron microscopy and mutational analysis for Escherichia coli proteins of the Clp family and FtsH, as well as for yeast Hsp104 (22)(23)(24)(25)(26)(27)(28)(29). However, no unfolding or threading activity has been described for p97/VCP, although it has been shown to suppress polyglutamine-induced protein aggregation in analogy to ClpB (30,31). In contrast, based on the crystal structure of mouse p97 it was suggested that threading through the pore is not possible, since the channel in D1 was blocked by a zinc ion (32,33).…”

mentioning

confidence: 84%

VAT, the Thermoplasma Homolog of Mammalian p97/VCP, Is an N Domain-regulated Protein Unfoldase

Gerega

Rockel

Peters

et al. 2005

Journal of Biological Chemistry

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The Thermoplasma VCP-like ATPase from Thermoplasma acidophilum (VAT) ATPase is a member of the two-domain AAA ATPases and homologous to the mammalian p97/VCP and NSF proteins. We show here that the VAT ATPase complex unfolds green fluorescent protein (GFP) labeled with the ssrA-degradation tag. Increasing the Mg 2؉ concentration derepresses the ATPase activity and concomitantly stimulates the unfolding activity of VAT. Similarly, the VAT⌬N complex, a mutant of VAT deleted for the N domain, displays up to 24-fold enhanced ATP hydrolysis and 250-fold enhanced GFP unfolding activity when compared with wild-type VAT. To determine the individual contribution of the two AAA domains to ATP hydrolysis and GFP unfolding we performed extensive site-directed mutagenesis of the Walker A, Walker B, sensor-1, and pore residues in both AAA domains. Analysis of the VAT mutant proteins, where ATP hydrolysis was confined to a single AAA domain, revealed that the first domain (D1) is sufficient to exert GFP unfolding indistinguishable from wild-type VAT, while the second AAA domain (D2), although active, is significantly less efficient than wild-type VAT. A single conserved aromatic residue in the D1 section of the pore was found to be essential for GFP unfolding. In contrast, two neighboring residues in the D2 section of the pore had to be exchanged simultaneously, to achieve a drastic inhibition of GFP unfolding.

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Analysis of the two p97/VCP/Cdc48p proteins of Caenorhabditis elegans and their suppression of polyglutamine-induced protein aggregation

Cited by 63 publications

References 46 publications

Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner

Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner

The Slow Wallerian Degeneration Protein, Wld^S, Binds Directly to VCP/p97 and Partially Redistributes It within the Nucleus

VAT, the Thermoplasma Homolog of Mammalian p97/VCP, Is an N Domain-regulated Protein Unfoldase

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Analysis of the two p97/VCP/Cdc48p proteins of Caenorhabditis elegans and their suppression of polyglutamine-induced protein aggregation

Cited by 63 publications

References 46 publications

Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner

Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner

The Slow Wallerian Degeneration Protein, WldS, Binds Directly to VCP/p97 and Partially Redistributes It within the Nucleus

VAT, the Thermoplasma Homolog of Mammalian p97/VCP, Is an N Domain-regulated Protein Unfoldase

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The Slow Wallerian Degeneration Protein, Wld^S, Binds Directly to VCP/p97 and Partially Redistributes It within the Nucleus