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Julie Rageul, Jennifer J Park, Ukhyun Jo, Alexandra S Weinheimer, Tri T M Vu, Hyungjin Kim
Multiple pathways counteract DNA replication stress to prevent genomic instability and tumorigenesis. The recently identified human SDE2 is a genome surveillance protein regulated by PCNA, a DNA clamp and processivity factor at replication forks. Here, we show that SDE2 cleavage after its ubiquitin-like domain generates Lys-SDE2Ct, the C-terminal SDE2 fragment bearing an N-terminal Lys residue. Lys-SDE2Ct constitutes a short-lived physiological substrate of the Arg/N-end rule proteolytic pathway, in which UBR1 and UBR2 ubiquitin ligases mediate the degradation...
January 30, 2019: Nucleic Acids Research
Dan Jia, Yuan Yuan Wang, Pin Wang, Yao Huang, David Yuke Liang, Dongmei Wang, Chuandong Cheng, Caihua Zhang, Lianying Guo, Pin Liang, Yang Wang, Yujie Jia, Cong Li
Prolonged parenchymal cell death leads to activation of fibrogenic cells and extracellular matrix accumulation and eventually liver fibrosis. Autophagy, a major catabolic process of intracellular degradation and recycling, participates in hepatic fibrosis. However, the precise role of autophagy in the pathogenesis of hepatic fibrosis is controversial. The present study aims to investigate the key role of small VCP/p97 interacting protein (SVIP) against CCl4 -induced hepatic fibrosis via activating autophagy...
January 25, 2019: Cell Death & Disease
Katarzyna Parzych, Paula Saavedra-García, Gabriel N Valbuena, Hibah A Al-Sadah, Mark E Robinson, Lucy Penfold, Desislava M Kuzeva, Angie Ruiz-Tellez, Sandra Loaiza, Viktoria Holzmann, Valentina Caputo, David C Johnson, Martin F Kaiser, Anastasios Karadimitris, Eric W-F Lam, Eric Chevet, Niklas Feldhahn, Hector C Keun, Holger W Auner
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues...
January 9, 2019: Oncogene
Xueyuan Wang, Enhe Bai, Hui Zhou, Sijia Sha, Hang Miao, Yanru Qin, Zhaogang Liu, Jia Wang, Haoyang Zhang, Meng Lei, Jia Liu, Ou Hai, Yongqiang Zhu
Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new molecule entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized...
December 28, 2018: Bioorganic & Medicinal Chemistry
Laura J Sharpe, Vicky Howe, Nicola A Scott, Winnie Luu, Lisa Phan, Jason M Berk, Mark Hochstrasser, Andrew J Brown
The E3 ligase membrane-associated ring-CH-type finger 6 (MARCH6) is a polytopic enzyme bound to the membranes of the endoplasmic reticulum. It controls levels of several known protein substrates, including a key enzyme in cholesterol synthesis, squalene monooxygenase. However, beyond its own autodegradation, little is known about how MARCH6 itself is regulated. Using CRISPR/Cas9 gene-editing, MARCH6 overexpression, and immunoblotting, we found here that cholesterol stabilizes MARCH6 protein endogenously and in HEK293 cells that stably express MARCH6...
December 13, 2018: Journal of Biological Chemistry
Francesca Cesaratto, Linda Sasset, Michael P Myers, Angela Re, Gianluca Petris, Oscar R Burrone
Translational stalling of ribosome bound to endoplasmic reticulum (ER) membrane requires an accurate clearance of the associated polypeptides, which is not completely understood in mammals. We characterized in mammalian cells the model of ribosomal stalling at the STOP-codon based on proteins tagged at the C-terminus with the picornavirus 2A peptide followed by a termination codon instead of the Proline (2A*). We exploited the 2A* stalling model to characterize the pathway of degradation of ER-targeted polypeptides...
October 24, 2018: Journal of Molecular Biology
Haiwen Li, Yu Cui, Jun Wei, Chao Liu, Yuhan Chen, Chun-Ping Cui, Lei Li, Xueli Zhang, Lingqiang Zhang
The bone morphogenetic protein (BMP)-Smad signaling pathway plays a crucial role in the control of bone homeostasis by regulating osteoblast activity. It is known that the ubiquitin ligase Smad ubiquitination regulatory factor (Smurf)1 is a master negative regulator of BMP signaling, but how its stability and activity are regulated remains poorly understood. Our study showed that valosin-containing protein/p97, the mutations of which lead to rare forms of Paget's disease of bone (PDB)-like syndrome-such as inclusion body myopathy (IBM) associated with Paget's disease of bone and frontotemporal dementia (IBM-PFD)-together with its adaptor nuclear protein localization (NPL)4, specifically interact with Smurf1 and deliver the ubiquitinated Smurf1 for degradation...
October 18, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Sandra Loaiza, Silvia A Ferreira, Tamara M Chinn, Alex Kirby, Elena Tsolaki, Camilla Dondi, Katarzyna Parzych, Adam P Strange, Laurent Bozec, Sergio Bertazzo, Martin A B Hedegaard, Eileen Gentleman, Holger W Auner
Cellular function depends on the maintenance of protein homeostasis (proteostasis) by regulated protein degradation. Chronic dysregulation of proteostasis is associated with neurodegenerative and age-related diseases, and drugs targeting components of the protein degradation apparatus are increasingly used in cancer therapies. However, as chronic imbalances rather than loss of function mediate their pathogenesis, research models that allow for the study of the complex effects of drugs on tissue properties in proteostasis-associated diseases are almost completely lacking...
November 2018: Biomaterials
Xiaonan Zhang, Paola Pellegrini, Amir Ata Saei, Ellin-Kristina Hillert, Magdalena Mazurkiewicz, Maria Hägg Olofsson, Roman A Zubarev, Pádraig D'Arcy, Stig Linder
Human cancers are characterized by intrinsic or acquired resistance to apoptosis and evasion of apoptosis has been proposed to contribute to treatment resistance. Bis-benzylidine piperidone compounds, containing α,β-unsaturated carbonyl functionalities, have been extensively documented as being effective in killing apoptosis-resistant cells and to display promising antineoplastic activities in a number of tumor models. We here explored the phenotypic response of colon cancer cells to b-AP15, a bis-benzylidine piperidone previously shown to inhibit the proteasome deubiquitinases (DUBs) USP14 and UCHL5...
August 25, 2018: Biochemical Pharmacology
Annette Aichem, Samira Anders, Nicola Catone, Philip Rößler, Sophie Stotz, Andrej Berg, Ricarda Schwab, Sophia Scheuermann, Johanna Bialas, Mira C Schütz-Stoffregen, Gunter Schmidtke, Christine Peter, Marcus Groettrup, Silke Wiesner
FAT10 is a ubiquitin-like modifier that directly targets proteins for proteasomal degradation. Here, we report the high-resolution structures of the two individual ubiquitin-like domains (UBD) of FAT10 that are joined by a flexible linker. While the UBDs of FAT10 show the typical ubiquitin-fold, their surfaces are entirely different from each other and from ubiquitin explaining their unique binding specificities. Deletion of the linker abrogates FAT10-conjugation while its mutation blocks auto-FAT10ylation of the FAT10-conjugating enzyme USE1 but not bulk conjugate formation...
August 20, 2018: Nature Communications
Ana C Bento, Claudia C Bippes, Corina Kohler, Charles Hemion, Stephan Frank, Albert Neutzner
Clearance of damaged mitochondria through mitophagy is critical for maintaining mitochondrial fidelity and the prevention of neurodegeneration. Here, we report on the UBX domain-containing, p97/VCP cofactor UBXD1/UBXN6/UBXDC2 and its role in mitophagy. Recognizing depolarized mitochondria via its C-terminal UBX domain, UBXD1 translocates to mitochondria in a Parkin-dependent manner. During Parkin-independent mitophagy, UBXD1 shows no mitochondrial translocation. Once translocated, UBXD1 recruits p97 to mitochondria via a bipartite binding motif consisting of its N-terminal VIM and PUB domains...
August 17, 2018: Scientific Reports
Qiao Lu, Jeff E Grotzke, Peter Cresswell
Dendritic cells use a specialized pathway called cross-presentation to activate CD8+ T cells by presenting peptides from exogenous protein antigens on major histocompatibility complex class I molecules. Considerable evidence suggests that internalized antigens cross endocytic membranes to access cytosolic proteasomes for processing. The mechanism of protein dislocation represents a major unsolved problem. Here we describe the development of a sensitive reporter substrate, an N-glycosylated variant of Renilla luciferase fused to the Fc region of human IgG1...
August 6, 2018: Nature Communications
David Mengel, Damiano Librizzi, Benedikt Schoser, Dieter Gläser, Christoph S Clemen, Richard Dodel, Rolf Schröder
Mutations of the human VCP gene, which encodes the V: alosin C: ontaining P: rotein (synonyms: p97, TER ATPase), are associated with various multi-systemic protein aggregation diseases. We report on a patient with progressive myopathy and incipient cognitive deficits. A diagnostic muscle biopsy revealed an inclusion body myopathy with protein aggregates. Magnetic resonance imaging and F18-positron-emission-tomography disclosed a fronto-temporal atrophy and glucose hypometabolism of the frontal and temporal lobes, respectively...
July 2018: Fortschritte der Neurologie-Psychiatrie
Monika Kustermann, Linda Manta, Christoph Paone, Jochen Kustermann, Ludwig Lausser, Cora Wiesner, Ludwig Eichinger, Christoph S Clemen, Rolf Schröder, Hans A Kestler, Marco Sandri, Wolfgang Rottbauer, Steffen Just
VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio)...
2018: Autophagy
Nicholas O Bodnar, Kelly H Kim, Zhejian Ji, Thomas E Wales, Vladimir Svetlov, Evgeny Nudler, John R Engen, Thomas Walz, Tom A Rapoport
Many polyubiquitinated proteins are extracted from membranes or complexes by the conserved ATPase Cdc48 (in yeast; p97 or VCP in mammals) before proteasomal degradation. Each Cdc48 hexamer contains two stacked ATPase rings (D1 and D2) and six N-terminal (N) domains. Cdc48 binds various cofactors, including the Ufd1-Npl4 heterodimer. Here, we report structures of the Cdc48-Ufd1-Npl4 complex from Chaetomium thermophilum. Npl4 interacts through its UBX-like domain with a Cdc48 N domain, and it uses two Zn2+ -finger domains to anchor the enzymatically inactive Mpr1-Pad1 N-terminal (MPN) domain, homologous to domains found in several isopeptidases, to the top of the D1 ATPase ring...
July 2018: Nature Structural & Molecular Biology
Asker Zeki Ozsoy, Sevil Cayli, Cansu Sahin, Seda Ocakli, Tuba Ozdemir Sanci, Delibas Bahri Ilhan
INTRODUCTION: Autophagy increases in placenta-related obstetrical diseases such as preeclampsia and intrauterine growth retardation but the regulation of autophagy by ubiquitin proteasome pathway (UPP) proteins, p97/Valosin containing protein (VCP) and ubiquitin (Ub) have not been previuosly studied in preeclampsia. The objective of this study is to investigate the expression of UPP (p97/VCP and Ub), autophagosomal (p62 and LC3) and autolysosomal proteins (Lamp1 and Lamp2) in the normal and preeclamptic human placentas and to explore the regulatory mechanism of these proteins in autophagic pathway...
July 2018: Placenta
Bruno Guedes Aguiar, Prasad K Padmanabhan, Carole Dumas, Barbara Papadopoulou
Valosin-containing protein (VCP)/p97/Cdc48 is one of the best-characterised type II cytosolic AAA+ ATPases most known for their role in ubiquitin-dependent protein quality control. Here, we provide functional insights into the role of the Leishmania VCP/p97 homologue (LiVCP) in the parasite intracellular development. We demonstrate that although LiVCP is an essential gene, Leishmania infantum promastigotes can grow with less VCP. In contrast, growth of axenic and intracellular amastigotes is dramatically affected upon decreased LiVCP levels in heterozygous and temperature sensitive (ts) LiVCP mutants or the expression of dominant negative mutants known to specifically target the second conserved VCP ATPase domain, a major contributor of the VCP overall ATPase activity...
October 2018: Cellular Microbiology
Yulia V Lyupina, Pavel A Erokhov, Oksana I Kravchuk, Alexander D Finoshin, Svetlana B Abaturova, Olga V Orlova, Svetlana N Beljelarskaya, Margarita V Kostyuchenko, Victor S Mikhailov
The protein VCP/p97 (also named CDC48 and TER94) belongs to a type II subfamily of the AAA+ATPases and controls cellular proteostasis by acting upstream of proteasomes in the ubiquitin-proteasome protein degradation pathway. The function of VCP/p97 in the baculovirus infection cycle in insect cells remains unknown. Here, we identified VCP/p97 in the fall armyworm Spodoptera frugiperda (Sf9) cells and analyzed the replication of the Autographa californica multiple nucleopolyhedrovirus, AcMNPV, in Sf9 cells in which the VCP/p97 function was inhibited...
July 15, 2018: Virus Research
Janica Lea Wiederstein, Hendrik Nolte, Stefan Günther, Tanja Piller, Martina Baraldo, Sawa Kostin, Wilhelm Bloch, Natalie Schindler, Marco Sandri, Bert Blaauw, Thomas Braun, Soraya Hölper, Marcus Krüger
Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSPs) that lead to muscle weakness. Here, we identify METTL21C as a skeletal muscle-specific lysine methyltransferase. Insertion of a β-galactosidase cassette into the Mettl21c mouse locus revealed that METTL21C is specifically expressed in MYH7-positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to age-dependent accumulation of autophagic vacuoles in skeletal muscle...
May 1, 2018: Cell Reports
Gorica Ristic, Joanna R Sutton, Kozeta Libohova, Sokol V Todi
Among the nine dominantly inherited, age-dependent neurodegenerative diseases caused by abnormal expansion in the polyglutamine (polyQ) repeat of otherwise unrelated proteins is Spinocerebellar Ataxia Type 3 (SCA3). SCA3 is caused by polyQ expansion in the deubiquitinase (DUB), ataxin-3. Molecular sequelae related to SCA3 remain unclear. Here, we sought to understand the role of protein context in SCA3 by focusing on the interaction between this DUB and Valosin-Containing Protein (VCP). VCP is bound directly by ataxin-3 through an arginine-rich area preceding the polyQ repeat...
August 2018: Neurobiology of Disease
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