Control of p97 function by cofactor binding

Buchberger, Alexander; Schindelin, Hermann; Hänzelmann, Petra

doi:10.1016/j.febslet.2015.08.028

Cited by 201 publications

(224 citation statements)

References 120 publications

(249 reference statements)

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“…Cdc48 is directed to different degradative pathways within the cell, where its activity is regulated and is dependent on the action of adaptor proteins -i.e. UBXdomain-containing proteins (Buchberger et al, 2015;Neuber et al, 2005;Schuberth and Buchberger, 2008). In yeast, there are seven UBX proteins.…”

Section: Discussionmentioning

confidence: 99%

Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

Pantazopoulou

Boban

Foisner

et al. 2016

Journal of Cell Science

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The nuclear envelope is a barrier comprising outer and inner membranes that separate the cytoplasm from the nucleoplasm. The two membranes have different physical characteristics and protein compositions. The processes governing the stability of inner nuclear membrane (INM) proteins are not well characterized. In Saccharomyces cerevisiae, the INM Asi1-Asi3 complex, principally composed of integral membrane proteins Asi1 and Asi3, is an E3 ubiquitin ligase. In addition to its well-documented function in endoplasmic reticulum (ER)-associated degradation, the Doa10 E3 ubiquitin ligase complex partially localizes to the INM. The Asi1-Asi3 and Doa10 complexes define independent INM-associated degradation (INMAD) pathways that target discrete sets of nuclear substrates for proteasomal degradation. Here, we report that Asi1 is rapidly turned over (t 1/2 ≤30 min). Its turnover depends on ubiquitinmediated degradation by nucleus-localized proteasomes, exhibiting a clear requirement for the E2 ubiquitin-conjugating enzyme Ubc7, Cue1 and the AAA ATPase Cdc48 and co-factor Ubx1. Asi1 turnover occurs largely independently of the Asi1-Asi3 or Doa10 complexes, indicating that it is subject to quality control at the INM in a manner distinct from that of the characterized INMAD pathways.

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Section: Discussionmentioning

confidence: 99%

Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

Pantazopoulou

Boban

Foisner

et al. 2016

Journal of Cell Science

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“…Defective SUMOylation of VCP Causes Altered Co-factor Binding, Impaired ERAD, and Increased Vulnerability to Stress Insults-VCP interacts with a large number of co-factors to exhort its diverse cellular functions, with most of the co-factors binding the N-domain of VCP (40). For example, VCP forms a complex with NPL4 and UFD1 to facilitate the degradation of polyubiquitinated protein substrates in ER stress (41).…”

Section: Defective Sumoylation Of Vcp Caused By Mutations Reduced Thementioning

confidence: 99%

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Wang

Qin

et al. 2016

Journal of Biological Chemistry

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Valosin-containing protein/p97(VCP) is a hexameric ATPase vital to protein degradation during endoplasmic reticulum stress. It regulates diverse cellular functions including autophagy, chromatin remodeling, and DNA repair. In addition, mutations in VCP cause inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD), as well as amyotrophic lateral sclerosis. Nevertheless, how the VCP activities were regulated and how the pathogenic mutations affect the function of VCP during stress are not unclear. Here we show that the small ubiquitin-like modifier (SUMO)-ylation of VCP is a normal stress response inhibited by the disease-causing mutations in the N-domain. Under oxidative and endoplasmic reticulum stress conditions, the SUMOylation of VCP facilitates the distribution of VCP to stress granules and nucleus, and promotes the VCP hexamer assembly. In contrast, pathogenic mutations in the VCP N-domain lead to reduced SUMOylation and weakened VCP hexamer formation upon stress. Defective SUMOylation of VCP also causes altered co-factor binding and attenuated endoplasmic reticulum-associated protein degradation. Furthermore, SUMO-defective VCP fails to protect against stress-induced toxicity in Drosophila. Therefore, our results have revealed SUMOylation as a molecular signaling switch to regulate the distribution and functions of VCP during stress response, and suggest that deficiency in VCP SUMOylation caused by pathogenic mutations will render cells vulnerable to stress insults.Valosin-containing protein (VCP/p97, cdc48, 2 is a highly conserved member of AAA (ATPase associated with diverse cellular activities) family proteins. It is mainly composed of N-domain and two ATPase domains. By forming a homohexamer and binding various co-factors via the N-domain, VCP helps to remodel, unfold, or degrade protein substrates using the energy derived from ATP hydrolysis (1-3). Due to its cellular abundance and broad interaction with a number of co-factors, key substrates, and regulators of the ubiquitin proteasome system, VCP has emerged as a vital modulator of a large variety of cellular activities, including protein degradation, ER stress response, autophagy/mitophagy, endosomal trafficking, cell cycle, and DNA repair (2, 5, 6). However, the factors that regulate VCP activities are not clear.The importance of VCP is also demonstrated by its association with cancer and degenerative diseases. VCP is highly expressed in non-small cell lung carcinoma (7), and its expression is correlated with tumor progression and prognosis (8). On the other hand, mutations in VCP have been associated with degenerative diseases, including inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS) (6, 9). Most pathogenic mutations of VCP are found in the N-domain, with a few in the ATPase domains (10). The pathology of VCP-associated degenerative diseases features ubiquitin-positive inclusions. Although some of the pathogenic VCP mutation...

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“…The function of VCP is modulated by "primary" binding proteins, of which about two dozen well-validated partners are known (21)(22)(23). Of particular interest is a set of adaptors that are thought to serve as specificity factors that link substrates to VCP.…”

Section: Protein Quality Control (Pqc)mentioning

confidence: 99%

Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor

Xue

Blythe

Freiberger

et al. 2016

Molecular & Cellular Proteomics

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Protein quality control (PQC) plays an important role in stemming neurodegenerative diseases and is essential for the growth of some cancers. Valosin-containing protein (VCP)/p97 plays a pivotal role in multiple PQC pathways by interacting with numerous adaptors that link VCP to specific PQC pathways and substrates and influence the post-translational modification state of substrates. However, our poor understanding of the specificity and architecture of the adaptors, and the dynamic properties of their interactions with VCP hinders our understanding of fundamental features of PQC and how modulation of VCP activity can best be exploited therapeutically. In this study we use multiple mass spectrometry-based proteomic approaches combined with biophysical studies to characterize the interaction of adaptors with VCP. Our results reveal that most VCP-adaptor interactions are characterized by rapid dynamics that in some cases are modulated by the VCP inhibitor NMS873. These findings have significant implications for both the regulation of VCP function and the impact of VCP inhibition on different VCP-adaptor complexes.

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Control of p97 function by cofactor binding

Cited by 201 publications

References 120 publications

Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor

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