UBXD7 Binds Multiple Ubiquitin Ligases and Implicates p97 in HIF1α Turnover

Alexandru, Gabriela; Graumann, Johannes; Smith, Graeme D; Kolawa, Natalie J.; Fang, Ruihua; Deshaies, Raymond J.

doi:10.1016/j.cell.2008.06.048

Cited by 289 publications

(409 citation statements)

References 63 publications

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“…Indeed, it was shown that immunoprecipitates of the UBA-UBX proteins FAF1, UBXD7, UBXD8 and SAKS1 contained not only p97, but also UFD1-NPL4 [49], an observation that is consistent with the existence of higher-order p97-cofactor complexes. A similar observation was made in yeast where the UBA-UBX protein Ubx2 was found to exist in a Cdc48 Ufd1-Npl4-Ubx2 complex [108].…”

Section: Higher Order Assembliessupporting

confidence: 58%

“…These UBA-UBX proteins serve as prototypical substrate-recruiting cofactors or substrate ''adaptors" of p97. So far, 13 UBX domain-containing proteins have been identified in mammals, all of which, with the exception of UBXD1 (see below), have been demonstrated to bind to p97 [46,47,49]. In addition, the related UBXL domain has been identified in a few p97 cofactors including the NPL4 subunit of the heterodimeric UFD1-NPL4 cofactor [50] and the two DUBs OTU1/YOD1 [51] and VCIP135 [52].…”

Section: Ubx and Ubxl Domainsmentioning

confidence: 99%

“…UBX domain containing proteins constitute the largest family of p97 cofactors [46,47]. A subset of UBX domain proteins is characterized by the presence of an ubiquitin-associated (UBA) domain, which mediates binding to ubiquitylated substrates [48,49]. These UBA-UBX proteins serve as prototypical substrate-recruiting cofactors or substrate ''adaptors" of p97.…”

Section: Ubx and Ubxl Domainsmentioning

confidence: 99%

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Control of p97 function by cofactor binding

2015

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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.

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Section: Higher Order Assembliessupporting

confidence: 58%

Section: Ubx and Ubxl Domainsmentioning

confidence: 99%

Section: Ubx and Ubxl Domainsmentioning

confidence: 99%

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Control of p97 function by cofactor binding

2015

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“…The phenotypes observed after co-depletion of Ube2S and UbcH10 are reminiscent of the strong mitotic delay caused by injection of a K11-deficient ubiquitin mutant into Xenopus embryos (11). A proteomic analysis revealed that p97/CDC48, whose depletion causes mitotic arrest in HeLa cells (39), efficiently binds K11-linked ubiquitin chains (40). K11-linked ubiquitin chains also accumulate in diseases with impaired proteasome activity, such as Huntington's or Alzheimer's (41), and they are abundant in normally dividing cells (12).…”

Section: Discussionmentioning

confidence: 99%

Identification of a physiological E2 module for the human anaphase-promoting complex

Williamson

Wickliffe

Mellone

et al. 2009

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

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Ubiquitination by the anaphase-promoting complex (APC/C) is essential for proliferation in all eukaryotes. The human APC/C promotes the degradation of mitotic regulators by assembling K11-linked ubiquitin chains, the formation of which is initiated by its E2 UbcH10. Here, we identify the conserved Ube2S as a K11-specific chain elongating E2 for human and Drosophila APC/C. Ube2S depends on the cell cycledependent association with the APC/C activators Cdc20 and Cdh1 for its activity. While depletion of Ube2S already inhibits APC/C in cells, the loss of the complete UbcH10/Ube2S-module leads to dramatic stabilization of APC/C substrates, severe spindle defects, and a strong mitotic delay. Ube2S and UbcH10 are tightly co-regulated in the cell cycle by APC/C-dependent degradation. We conclude that UbcH10 and Ube2S constitute a physiological E2-module for APC/C, the activity of which is required for spindle assembly and cell division.K11-linked chain ͉ proteasome ͉ ubiquitin

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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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UBXD7 Binds Multiple Ubiquitin Ligases and Implicates p97 in HIF1α Turnover

Cited by 289 publications

References 63 publications

Control of p97 function by cofactor binding

Control of p97 function by cofactor binding

Identification of a physiological E2 module for the human anaphase-promoting complex

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

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