The AAA-ATPase Cdc48/p97 Regulates Spindle Disassembly at the End of Mitosis

Cao, Kan; Nakajima, Reiko; Meyer, Hemmo; Zheng, Yixian

doi:10.1016/s0092-8674(03)00815-8

Cited by 188 publications

(171 citation statements)

References 58 publications

(4 reference statements)

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“…These observations suggest that the CDC-48 UFDϪ1/NPLϪ4 complex is crucial for DNA replication initiation, which might not involve a role in CDT-1 turnover. Several previous studies have described different activities of Cdc48/p97 in mitotic events, such as spindle disassembly and nuclear envelope reformation (6,7,10,11). Here, we identified a role for CDC-48 UFDϪ1/NPLϪ4 in DNA replication, which is important for cell cycle progression (Fig.…”

Section: Resultsmentioning

confidence: 54%

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Cell cycle progression requires the CDC-48 ^{UFD−1/NPL−4} complex for efficient DNA replication

Mouysset

Deichsel

Moser

et al. 2008

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

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Since cdc48 mutants were isolated by the first genetic screens for cell division cycle (cdc) mutants in yeast, the requirement of the chaperone-like ATPase Cdc48/p97 during cell division has remained unclear. Here, we discover an unanticipated function for Caenorhabditis elegans CDC-48 in DNA replication linked to cell cycle control. Our analysis of the CDC-48 UFD؊1/NPL؊4 complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms. These developmental defects result from activation of the DNA replication checkpoint caused by replication stress. Similar to loss of replication licensing factors, DNA content is strongly reduced in worms depleted for CDC-48, UFD-1, and NPL-4. In addition, these worms show decreased DNA synthesis and hypersensitivity toward replication blocking agents. Our findings identified a role for CDC-48 UFD؊1/NPL؊4 in DNA replication, which is important for cell cycle progression and genome stability.ATL-1/ATR ͉ C. elegans ͉ CDC-48/p97 ͉ genome stability M any biological processes including development and cell division are tightly controlled by ubiquitin-mediated protein degradation. A central factor for mobilizing and targeting ubiquitylated substrates to the 26S proteasome is Cdc48/p97 (Cdc48 in yeast, CDC-48 in C. elegans, p97 in mammals), a chaperone-like AAA ATPase (1). Its activity is modulated by alternative adaptor proteins, which determine recruitment and processing of specific substrates. Cdc48/p97 forms a complex with the cofactors Ufd1 and Npl4 that is involved in endoplasmic reticulum (ER)-associated protein degradation (ERAD) (2), membrane fusion and cell cycle progression (3, 4). Temperature sensitive cdc48 mutants have already been isolated by early cdc-screens (5) in Saccharomyces cerevisiae. However, the essential role of Cdc48 during cell cycle progression remained elusive.Meanwhile, different activities of Cdc48/p97 in mitosis have been addressed by several studies. Early observations in yeast and recent findings using Xenopus egg extracts suggested that Cdc48/p97 regulates spindle disassembly during exit from mitosis (6, 7). For example, spindle regulators such as the Polo-like kinase Plx remain attached and probably stabilize the spindle in the absence of p97 Ufd1/Npl4 . However, contradictory evidence exists concerning a specific role of the p97 Ufd1/Npl4 complex in spindle dynamics (8,9). Beside spindle function, p97 together with its Ufd1-Npl4 cofactor is important for nuclear envelope assembly (10). Interestingly, it has been shown that p97 stimulates nucleus reformation after mitosis by extracting and thereby inactivating the mitotic progression kinase Aurora B from chromatin (11). Together, these diverse processes involving Cdc48/p97 suggest the existence of multiple substrates that need to be regulated during mitosis.Recently, we found that the C. elegans Cdc48/p97 homologues CDC-48.1 and CDC-48.2 form an evolutionarily conserved complex with UFD-1 and NPL-4 important for t...

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Section: Resultsmentioning

confidence: 54%

“…Early observations in yeast and recent findings using Xenopus egg extracts suggested that Cdc48/p97 regulates spindle disassembly during exit from mitosis (6,7). For example, spindle regulators such as the Polo-like kinase Plx remain attached and probably stabilize the spindle in the absence of p97 Ufd1/Npl4 .…”

mentioning

confidence: 99%

Cell cycle progression requires the CDC-48 ^{UFD−1/NPL−4} complex for efficient DNA replication

Mouysset

Deichsel

Moser

et al. 2008

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

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“…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)(10)(11)(12)(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 (16).…”

Section: Intracellular Immunity | Cdc48mentioning

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.

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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...

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“…Studies in Xenopus egg extracts have shown that CDC48/p97/VCP-Ufd1-Npl4 complex-mediated disassembly of mitotic spindles is through its interaction with XMAP215 and TPX2 and regulates their binding to microtubules at mitotic exit (6). This regulation is independent of XMAP215 and TPX2 degradation.…”

mentioning

confidence: 99%

AAA ATPase p97/Valosin-containing Protein Interacts with gp78, a Ubiquitin Ligase for Endoplasmic Reticulum-associated Degradation

Zhong

Shen

Ballar

et al. 2004

Journal of Biological Chemistry

196

194

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Endoplasmic reticulum-associated degradation (ERAD)is a protein quality control mechanism that eliminates unwanted proteins from the endoplasmic reticulum (ER) through a ubiquitin-dependent proteasomal degradation pathway. gp78 is a previously described ER membrane-anchored ubiquitin ligase (E3) involved in ubiquitination of ER proteins. AAA ATPase (ATPase associated with various cellular activities) p97/valosincontaining protein (VCP) subsequently dislodges the ubiquitinated proteins from the ER and chaperones them to the cytosol, where they undergo proteasomal degradation. We now report that gp78 physically interacts with p97/VCP and enhances p97/VCP-polyubiquitin association. The enhanced association correlates with decreases in ER stress-induced accumulation of polyubiquitinated proteins. This effect is abolished when the p97/VCP-interacting domain of gp78 is removed. Further, using ERAD substrate CD3␦, gp78 consistently enhances p97/VCP-CD3␦ binding and facilitates CD3␦ degradation. Moreover, inhibition of endogenous gp78 expression by RNA interference markedly increases the levels of total polyubiquitinated proteins, including CD3␦, and abrogates VCP-CD3␦ interactions. The gp78 mutant with deletion of its p97/VCP-interacting domain fails to increase CD3␦ degradation and leads to accumulation of polyubiquitinated CD3␦, suggesting a failure in delivering ubiquitinated CD3␦ for degradation. These data suggest that gp78-p97/VCP interaction may represent one way of coupling ubiquitination with retrotranslocation and degradation of ERAD substrates.

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The AAA-ATPase Cdc48/p97 Regulates Spindle Disassembly at the End of Mitosis

Cited by 188 publications

References 58 publications

Cell cycle progression requires the CDC-48 ^{UFD−1/NPL−4} complex for efficient DNA replication

Cell cycle progression requires the CDC-48 ^{UFD−1/NPL−4} complex for efficient DNA replication

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

AAA ATPase p97/Valosin-containing Protein Interacts with gp78, a Ubiquitin Ligase for Endoplasmic Reticulum-associated Degradation

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The AAA-ATPase Cdc48/p97 Regulates Spindle Disassembly at the End of Mitosis

Cited by 188 publications

References 58 publications

Cell cycle progression requires the CDC-48 UFD−1/NPL−4 complex for efficient DNA replication

Cell cycle progression requires the CDC-48 UFD−1/NPL−4 complex for efficient DNA replication

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

AAA ATPase p97/Valosin-containing Protein Interacts with gp78, a Ubiquitin Ligase for Endoplasmic Reticulum-associated Degradation

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Cell cycle progression requires the CDC-48 ^{UFD−1/NPL−4} complex for efficient DNA replication

Cell cycle progression requires the CDC-48 ^{UFD−1/NPL−4} complex for efficient DNA replication